Diazepam-zn

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DIAZEPAM-ZN (DIAZEPAM-ZN)

Composition:

Active substance: diazepam;

1 tablet contains 5 mg of diazepam;

Excipients: maize starch; lactose monohydrate; magnesium stearate; talc; microcrystalline cellulose.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: white or almost white, round cylindrical tablets with a flat surface and bevelled edges.

Pharmacotherapeutic group.

Anxiolytics. Benzodiazepine derivatives. ATC code N05BA01.

Pharmacological properties.

Pharmacodynamics.

Diazepam exerts its effects by enhancing GABA-ergic (GABA – gamma-aminobutyric acid) neurotransmission at the synaptic level, primarily in the limbic system, subcortical structures, thalamus, and hypothalamus. GABA is the main neurotransmitter of the central nervous system (CNS). The allosteric site of the GABAA receptor is the binding site for CNS depressants such as benzodiazepines, including diazepam. Benzodiazepine receptor agonists exhibit anxiolytic, anticonvulsant, sedative, hypnotic, and muscle relaxant effects. They do not cause general neuronal blockade.

Binding of benzodiazepines to the GABAA receptor increases the receptor's sensitivity to GABA. As a result, the chloride ion channels of the receptor complex remain in the activated state for a longer period, allowing a greater influx of chloride ions into the neuron. This enhances the degree of hyperpolarization of the cell membrane and inhibits signal transmission.

Pharmacokinetics.

Diazepam is well and rapidly absorbed from the gastrointestinal tract, reaching peak plasma concentrations within 30–90 minutes. It is highly bound to plasma proteins (approximately 99%), is highly lipophilic, and readily crosses the blood-brain barrier. The main metabolites are N-desmethyldiazepam (nordazepam) and oxazepam. Diazepam and nordazepam undergo slow hydroxylation to form other active metabolites, such as oxazepam. The prolonged elimination half-life of nordazepam (approximately 60 hours) contributes to the extended duration of action of the drug. With prolonged use, there is a relative accumulation of nordazepam in the body. Hepatic metabolism of diazepam also produces the metabolite temazepam. Plasma concentrations of diazepam decline in two phases: after an initial rapid elimination phase with a half-life of about 1 hour, a terminal elimination phase follows, lasting approximately 24–48 hours, prolonged by the presence of active metabolites. Diazepam is excreted in urine, primarily as free and conjugated metabolites. In neonates, elderly individuals, and patients with hepatic or renal impairment, the elimination half-life may be prolonged several-fold. Diazepam and its metabolites cross the placental barrier and are excreted into breast milk.

Clinical characteristics.

Indications.

Adults.

Episodic or temporary treatment of anxiety disorders.

Insomnia.

Relief of muscle spasms associated with cerebral etiology.

As part of complex treatment of epilepsy.

Premedication in minor surgical procedures.

Benzodiazepines are indicated only when the problem is severe, interferes with a person's lifestyle, or significantly complicates it.

Contraindications.

• Hypersensitivity to benzodiazepines or to any component of the medicinal product.
• Severe respiratory insufficiency.
• Severe hepatic and renal insufficiency.
• Sleep apnea syndrome.
• Myasthenia gravis.
• Phobic or obsessive conditions, chronic psychoses, alcohol or drug dependence.
• Closed-angle glaucoma and acute glaucoma attack.
• Pregnancy or breastfeeding period.
• Intoxication with alcohol or other psychotropic substances.
• Must not be used as the primary treatment for psychotic states.
• Cannot be used for treatment of depression and anxiety caused by depression.

Interaction with other medicinal products and other forms of interaction.

Oxidative metabolism of diazepam is mediated by CYP3A and CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated with glucuronic acid. Substances that are modulators of CYP3A and/or CYP2C19 may potentially alter the pharmacokinetics of diazepam. Concomitant use of sedative medications such as benzodiazepines or related agents with opioids increases the risk of sedation, respiratory depression, hemodynamic instability, coma, and death due to additive CNS depressant effects. When these agents are used together, dosage and duration of use should be limited (see section "Special precautions for use").

Other psychotropic agents (e.g., anxiolytics, hypnotics, neuroleptics, monoamine oxidase inhibitors, and other antidepressants) and anticonvulsants, narcotics, narcotic analgesics, and sedative antihistamines may potentiate the effect of the medicinal product.

Alcohol enhances the sedative effect of the drug. This affects the ability to drive vehicles and operate machinery (see section "Ability to influence reaction rate when driving vehicles or operating other machinery").

Diazepam, especially with prolonged use, may interact with drugs metabolized by cytochrome CYP3A and CYP2C19 (e.g., cimetidine, ketoconazole, fluconazole, itraconazole, voriconazole, fluvoxamine, fluoxetine, omeprazole, isoniazid, erythromycin, disulfiram, fosamprenavir, ritonavir, oral contraceptives), resulting in reduced clearance of diazepam and enhanced and prolonged sedative effect. Enzyme inducers (e.g., rifampicin), including antiepileptic agents (e.g., carbamazepine, phenytoin), may accelerate the elimination of diazepam. A similar effect on diazepam metabolism may be caused by tobacco smoking.

Concomitant use with other muscle relaxants leads to unpredictable effects and increases the risk of apnea.

Diazepam enhances the effect of antihypertensive agents. When used concomitantly with moxonidine, the sedative effect of diazepam is enhanced. Muscle relaxants (baclofen or tizanidine), α-agonists (lofexidine), the antiemetic nabilone, and the gastrointestinal stimulant cisapride also enhance the sedative effect.

In low doses, theophylline reduces the sedative effect of benzodiazepines.

Diazepam interacts with levodopa (tending to weaken its effect), with phenytoin, and with agents that reduce skeletal muscle hypertonus (promoting enhancement of their action).

Benzodiazepines may enhance the adverse/toxic effects of clozapine. Therefore, prior to initiating clozapine therapy, consideration should be given to reducing the dose (or discontinuing) benzodiazepine.

Benzodiazepines may enhance the CNS depressant effect of sodium oxybate.

Special precautions for use.

Before initiating treatment with Diazepam-ZN, the physician should conduct a thorough assessment of existing disorders.

If the patient does not experience improvement within 7–14 days of treatment or experiences a relapse of insomnia, this should be reported to the physician.

General information regarding observed effects following treatment with benzodiazepines and other similar-acting drugs, which should be considered when using the medicinal product Diazepam-ZN, is provided below.

Tolerance

Regular use of benzodiazepines or similar-acting drugs, including diazepam, over several weeks may lead to reduced effectiveness of their action.

Drug dependence

Use of benzodiazepines or similar-acting drugs may lead to the development of psychological and physical dependence. The risk of developing drug dependence increases with dose and duration of treatment, and is higher in patients with alcohol dependence, a history of substance dependence, or personality disorders. Such patients require regular monitoring; repeated prescriptions should be avoided, and treatment should be discontinued gradually. After physical dependence has developed, abrupt discontinuation of benzodiazepines is accompanied by withdrawal syndrome. Characteristic manifestations of withdrawal syndrome include headache, tremor, muscle pain, increased anxiety, tension, attention deficit, psychomotor agitation, sleep disturbances (including insomnia), confusion, and irritability. Perceptual disturbances, dizziness, palpitations, loss of appetite, nausea, vomiting, sweating, muscle and abdominal spasms may also occur, and rarely delirium and recurrent seizures. In severe cases derealization, depersonalization, hyperacusis, tactile and light hyperesthesia, tingling and numbness of extremities, hallucinations, or epileptic seizures may appear.

Rebound anxiety and restlessness

After short-term discontinuation of diazepam treatment, a rebound phenomenon may occur. This means that symptoms which prompted benzodiazepine treatment return or reappear in a more intense form. This may also be accompanied by other reactions such as mood changes, anxiety, sleep disturbances, and restlessness. Since the risk of withdrawal symptoms/rebound symptoms is higher with abrupt discontinuation of treatment, gradual dose reduction is recommended. Withdrawal symptoms may occur during several days after completion of treatment.

Duration of treatment

The duration of treatment should be as short as possible, depending on the indication. In case of oral administration, treatment duration should not exceed 4 weeks for insomnia, and 8–12 weeks for anxiety states, including the tapering period. In some cases, treatment longer than recommended may be necessary. The condition for prolonged treatment is repeated assessment of the patient's condition.

At the beginning of treatment, it is important to inform patients that treatment will be short-term and clearly explain the necessity of gradual dose reduction. For patient safety, patients should be warned not to increase the dose on their own and not to discontinue the drug abruptly without physician approval. Additionally, patients should be informed about the possible occurrence of withdrawal syndrome to reduce anxiety, especially when discontinuing therapy.

Anterograde amnesia

Diazepam, like benzodiazepines and similar drugs, may cause anterograde amnesia. Anterograde amnesia may occur with therapeutic doses, and the risk increases with higher doses. The condition most commonly manifests within several hours after oral administration of benzodiazepines; therefore, to reduce the risk, patients should be allowed uninterrupted sleep of 7–8 hours.

Paradoxical reactions

During use of benzodiazepines, paradoxical reactions such as restlessness, excitement, anxiety, irritability, aggression, increased muscle tone, delirium, anger, nightmares, insomnia, hallucinations, psychoses, somnambulism, personality disturbances, pronounced inappropriate behavior, and other behavioral disorders may occur. If such symptoms appear, the drug should be discontinued immediately. These reactions are observed significantly more frequently in elderly patients.

Risk of concomitant use with opioids

Combined use of diazepam and opioids may result in sedation, respiratory depression, coma, and death. Due to these risks, concomitant prescription of sedative drugs such as benzodiazepines (or related drugs) with opioids should only be considered for patients for whom alternative treatment options are not feasible. If the decision is made to prescribe diazepam and opioids together, the lowest effective dose should be used for the shortest possible duration (see also recommendations on general use in the section "Dosage and administration").

Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. In such cases, it is strongly recommended to inform patients and caregivers (if any) about these symptoms.

Concomitant use of alcohol/CNS depressants

During treatment with Diazepam-ZN, alcohol and/or other CNS depressants must not be consumed. This combination potentiates the clinical effects of benzodiazepines, including severe sedative effects, clinically associated with respiratory and/or cardiovascular depression.

Diazepam may be used in patients with a history of drug or alcohol dependence or substance abuse only if other treatment methods are ineffective and only with extreme caution under close supervision, as their risk of developing benzodiazepine dependence and drug abuse is higher. In other cases, the use of benzodiazepines should be avoided.

Special patient groups

The appropriateness of using the medicinal product should be carefully considered in cases of respiratory insufficiency or reduced mental capacity due to the risk of respiratory depression.

For patients with impaired renal or hepatic function, chronic respiratory insufficiency, elderly patients, or debilitated patients, dosage should be determined with particular caution; lower doses with longer intervals should be used. Elderly patients have increased sensitivity to benzodiazepines, prolonged elimination, and enhanced sedative effects, thus increasing the risk of cognitive disorders (memory impairment) and hypotonia (falls).

Diazepam should be used with caution in patients with porphyria. Use of diazepam may provoke exacerbation of symptoms of this disease.

When treating patients with mild to moderate renal impairment, standard precautionary measures should be observed.

Use of benzodiazepines and similar drugs is not recommended in patients with severe hepatic insufficiency, as these drugs may accelerate the development of hepatic encephalopathy. Doses should be reduced in patients with chronic liver disease.

Other

During treatment with diazepam and for 3 days thereafter, consumption of any alcoholic beverages is prohibited.

Benzodiazepines are not recommended for the treatment of psychotic disorders.

Benzodiazepines should not be used to treat depression or anxiety caused by depression (possible increase in suicidal thoughts/behavior in these patients).

Diazepam is contraindicated in closed-angle glaucoma and acute glaucoma attacks, but may be used in open-angle glaucoma provided appropriate treatment is administered.

With prolonged use, liver function tests should be monitored, and blood analysis (morphological analysis with blood smear) should be performed. Patients taking diazepam should be warned about the synergistic interaction between the drug and alcohol, as well as other psychotropic agents.

Excipients

If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

Use during pregnancy or breastfeeding.

The medicinal product should not be used during pregnancy or breastfeeding.

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 must inform their physician if they become pregnant or suspect pregnancy.

Ability to affect reaction speed when driving or operating machinery.

Benzodiazepines may impair decision-making ability and increase reaction time, negatively affecting the ability to drive or operate machinery.

During the initial phase of using the medicinal product, driving, and engaging in activities involving risk of accidents (e.g., operating machinery, working at heights) are prohibited for 12–24 hours after administration, as this may be potentially dangerous. Thereafter, the extent of restriction should be determined individually, taking into account the elimination time, which may be several times longer, especially in elderly patients and patients with impaired renal or hepatic function. Consumption of alcohol is prohibited during use of the medicinal product and throughout its duration of action.

Method of Administration and Dosage

Dosage and duration of treatment should be individually adjusted for each patient.

Treatment should be initiated at the lowest effective dose appropriate for 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, the patient must be informed that therapy will be of limited duration, and the schedule for gradual dose reduction should be explained. To reduce anxiety related to the possible occurrence of rebound phenomena, the patient should be aware that such effects may occur during treatment (see section "Special Warnings and Precautions for Use").

It should be noted that when using benzodiazepines with short duration of action, symptoms of withdrawal syndrome may appear 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 developing withdrawal syndrome.

Adults

Anxiety states |anxiety|: the usual dose for adults is 5 mg. The maximum dose is up to 30 mg per day in divided doses. The dosing regimen should be individually determined by the physician.|milligram-equivalents|

Insomnia associated with anxiety in adults: 5–15 mg|milligram-equivalents| taken half an hour before bedtime.

The lowest effective doses that relieve symptoms should be used.

Full-dose treatment 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. For patients who have used benzodiazepines for a prolonged period, a longer tapering period may be required. Dose reduction should only be performed by a physician.

Spastic conditions|deficits| of muscles: muscle spasms – 5–15 mg|milligram-equivalents| per day, divided into doses of 5 mg 1–3 times daily; in individual cases of cerebral origin spasms – 5–60 mg per day in several divided doses.|severe|

Premedication: 5–20 mg.

Elderly Patients

Elderly patients are more sensitive to drugs acting on the CNS. Doses used should not exceed half of the dose recommended for adult patients.

Patients with|with| mild or moderate hepatic and/or renal impairment

Caution should be exercised when treating patients with mild or moderate impairment of liver and/or kidney function. Dose reduction may be necessary.

Dosage should be individually adjusted depending on the degree|extent| of impairment of the affected organ.

Children.

The medicinal product Diazepam-ZN, 5 mg tablets, cannot be used in children due to the inability to accurately dose (tablet splitting).

Overdose.

In case of overdose, somnolence, ataxia, dysarthria, nystagmus, arterial hypotension, CNS depression with symptoms of muscle weakness, confusion, decreased mental activity, and rarely paradoxical excitation may occur. Overdose with this medicinal product rarely causes life-threatening effects; however, severe overdose may lead to coma, areflexia, circulatory and respiratory depression, and apnea. Respiratory depression caused by benzodiazepines in patients with respiratory disorders tends to be more severe.

Benzodiazepines enhance the effects of other CNS depressants, including alcohol.

Continuous monitoring of circulation, respiration, and renal function is required.

General symptomatic and supportive treatment should be applied, including ensuring airway patency, intravenous fluid administration, mechanical ventilation if necessary, circulatory support, and administration of vasoactive agents. Flumazenil may be used as a specific benzodiazepine receptor antagonist.

Due to the risk of epileptic seizures, caution is required when administering flumazenil to patients with epilepsy treated with benzodiazepines such as diazepam, or to patients dependent on benzodiazepines.

Dialysis has minimal effect on the elimination of diazepam.

Adverse reactions.

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

Undesirable adverse effects listed in the table below are based on both clinical trial results and post-marketing reports. Adverse effects of the drug obtained from post-marketing experience with diazepam originate from spontaneous case reports and literature. Since these adverse event reports are voluntary and derived from a population of unknown size, it is not possible to reliably estimate their frequency.

Rarely observed: coordination disturbances, confusion, dizziness, headache, mood deterioration, blurred vision, accommodation disorders, skin rash, autonomic disturbances, constipation, speech disorders, decreased blood pressure, urinary retention and disorders of micturition, nausea, dry mouth or increased salivation, flushing, tremor, changes in libido, bradycardia.

Very rarely reported: increased levels of transaminases and alkaline phosphatase, jaundice, and neutropenia. In patients receiving benzodiazepines, falls and bone fractures have been reported. The risk is increased when sedatives (particularly alcoholic beverages) are used concomitantly and in elderly individuals.

Description of some adverse effects

Somnolence, emotional exhaustion, reduced attention, confusion, fatigue, headache, dizziness, muscle weakness, ataxia, or diplopia — these phenomena occur mainly at the beginning of treatment and usually disappear with repeated administration. Other adverse effects such as gastrointestinal disturbances, changes in libido, and skin reactions have occasionally been reported.

Amnesia

Anterograde amnesia may occur at therapeutic doses, with the risk increasing as the dose increases. The amnestic effect may be associated with inappropriate behavior (see section "Special precautions").

Depression

Pre-existing depression may emerge during treatment with benzodiazepines.

Psychiatric and paradoxical reactions

It is known that treatment with benzodiazepines and benzodiazepine-like drugs may lead to restlessness, excitement, irritability, aggressiveness, feelings of frustration, hysteria, delirium, anger, nightmares, hallucinations, psychoses, inappropriate behavior, and other undesirable behavioral reactions. With this medicinal product, these symptoms may be quite severe. They occur more frequently in elderly patients.

Dependence

Use of the drug (even at therapeutic doses) may lead to physical dependence: discontinuation of treatment may result in withdrawal syndrome or may cause rebound symptoms (see section "Special precautions"). Psychological dependence may also develop. Abuse of benzodiazepines has also been reported.

Reporting of suspected adverse reactions

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

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 in a blister; 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu"".

Manufacturer's location and address of its business activity.

41, Kuilikivska Street, Kharkiv, Kharkiv region, 61002, Ukraine.