Lozeta

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOZETA (LOZETA)

Composition:

Active substance: lorazepam;

1 tablet contains micronized lorazepam 0.5 mg or 1 mg or 2.5 mg;

Excipients:

tablets of 0.5 mg: lactose monohydrate; microcrystalline cellulose (type 102); sodium starch glycolate (type A); magnesium stearate;

tablets of 1 mg: lactose monohydrate; microcrystalline cellulose (type 102); sodium starch glycolate (type A); magnesium stearate;

tablets of 2.5 mg: lactose monohydrate; microcrystalline cellulose (type 102); sodium starch glycolate (type A); magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

tablets of 0.5 mg: white or almost white, round, flat tablets.

tablets of 1 mg: white or almost white, round, flat tablets, with a score on one side and engraved number "1" on the other side.

tablets of 2.5 mg: white or almost white, round, flat tablets, with a score on one side and engraved number "2.5" on the other side.

Pharmacotherapeutic group. Medicines for treatment of the nervous system. Psycholeptics. Anxiolytics. Benzodiazepine derivatives. Lorazepam. ATC code N05B A06.

Pharmacological Properties

Pharmacodynamics

The active substance, lorazepam, belongs to the benzodiazepine class of drugs. It is a tranquilizer with intermediate duration of action, exerting therapeutic effects even at low doses. The anxiolytic and anticonvulsant effects of lorazepam are pronounced, particularly at higher doses, while its sedative and especially myorelaxant effects are relatively weak. By reducing emotional factors, lorazepam eliminates conditions conducive to the development of diseases caused by emotional and psychoreactive factors. When administered as a single nighttime dose, the drug has a hypnotic effect. The pharmacological action of benzodiazepines is due to their high affinity for receptors of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Benzodiazepines enhance the action of GABA, leading to the opening of chloride channels in cell membranes and increased GABAergic inhibitory neurotransmission.

Pharmacokinetics

Absorption
After administration, lorazepam is almost completely absorbed (95%). Maximum blood concentration is reached within 2–3 hours after intake. Following a single dose, the maximum plasma concentration of lorazepam is approximately 10–15 ng/mL.

Distribution
Protein binding of lorazepam is about 90%. The volume of distribution of protein-bound lorazepam ranges from 0.3 to 1.3 L/kg, while that of unbound lorazepam is 10.4 L/kg in young patients and 8.6 L/kg in elderly patients. Lorazepam crosses the placental barrier and is found in breast milk in negligible amounts.

Metabolism
Lorazepam is inactivated by more than 90% via conjugation with glucuronic acid. These metabolites are pharmacologically inactive. Lorazepam undergoes minimal hydroxylation and is not subject to N-dealkylation by the cytochrome P450 enzyme system.

Elimination
The glucuronide metabolite of lorazepam is excreted in urine by more than 85%. Approximately 1% of the administered dose is excreted unchanged by the kidneys. Lorazepam and its glucuronide are excreted in feces in negligible amounts. The elimination half-life of lorazepam averages 12–16 hours.

Pharmacokinetics in Specific Patient Groups

Elderly patients: Studies involving elderly and younger patients have demonstrated age-dependent differences in lorazepam pharmacokinetics.

Hepatic impairment: In patients with liver disease (e.g., hepatitis, alcoholic cirrhosis), no significant changes in pharmacokinetic parameters have been observed.

Renal impairment: In patients with renal insufficiency, the metabolic clearance of lorazepam and plasma concentrations of unbound lorazepam remain within normal limits. However, an increased elimination half-life of lorazepam glucuronide has been observed, and this inactive metabolite may accumulate. With subchronic dosing, elimination of unbound lorazepam may also be altered.

Clinical characteristics.

Indications.

• Symptomatic short-term treatment of anxiety, tension and agitation, and sleep disturbances caused by these conditions.
• Premedication before diagnostic procedures, as well as before and after surgery.

Note

Pharmacological treatment is not required for all conditions associated with anxiety, tension and agitation, or for sleep disturbances. These are often manifestations of physical or mental disorders and can be managed by other interventions or by treating the underlying condition. Anxiety and tension due to ordinary everyday stress usually should not be treated with sedatives. The use of lorazepam as a hypnotic is justified only if the daytime effect of a benzodiazepine is simultaneously desired.

Contraindications.

• Hypersensitivity to the active substance, other benzodiazepines, or to any of the excipients;
• Patients with a history of dependence;
• Myasthenia gravis;
• Spinal and cerebellar ataxia;
• Acute alcohol intoxication or poisoning with central nervous system (CNS) depressants (e.g., hypnotics or analgesics, neuroleptics, antidepressants, and lithium);
• Respiratory impairment (e.g., sleep apnea syndrome, chronic obstructive pulmonary disease);
• Severe hepatic insufficiency.

Children and adolescents under 18 years of age should not be treated with lorazepam, except for urgent indications for sedation before diagnostic procedures, as well as before and after surgery. Lorazepam is not recommended for children under 6 years of age.

Interaction with other medicinal products and other forms of interaction.

Unrecommended interactions

• Alcohol. Lorazepam should not be taken with alcohol (enhanced sedative effect; impaired ability to drive or operate machinery).
• Sodium oxybate. Concomitant use should be avoided (enhanced effect of sodium oxybate).
• HIV protease inhibitors. Concomitant use should be avoided (increased risk of prolonged sedation - see below regarding zidovudine use).

Interactions requiring attention

• Opioids: concomitant use of sedative medicinal products such as benzodiazepines or related substances like lorazepam with opioids increases the risk of sedation, respiratory depression, coma, and fatal outcome due to additive CNS depressant effects. Dose and duration of concomitant use should be limited (see section "Special precautions").
• Central-acting medicinal products: central depressive effects may be enhanced if lorazepam is combined with agents such as neuroleptics, antipsychotics, tranquilizers, antidepressants, hypnotics, analgesics, anesthetics, barbiturates, and sedating antihistamines. Elderly patients may require special monitoring.
• Antiepileptic drugs: pharmacokinetic studies on possible interactions between benzodiazepines and antiepileptic drugs have yielded conflicting results. Both decreased and increased levels of lorazepam, as well as no changes, have been reported.

Concomitant administration of phenobarbital may lead to additional CNS effects. Dose selection should be particularly cautious during initial treatment stages.

Side effects may be more pronounced when hydantoins or barbiturates are used.

Valproate may inhibit glucuronidation of lorazepam (increased serum levels: increased risk of drowsiness).

• Narcotic analgesics: enhanced euphoria may lead to increased psychological dependence.
• Clozapine: reports of marked sedation, excessive salivation, hypotension, ataxia, delirium, and respiratory arrest with concomitant use of lorazepam.
• Muscle relaxants: when taken with muscle relaxants, the overall muscle-relaxing effect may be enhanced (cumulative), so caution is recommended, especially in elderly patients and when higher doses are used (risk of falls, see section "Special precautions").
• Other medicinal products that enhance the sedative effect of lorazepam: cisapride, lofexidine, nabilone, disulfiram, and muscle relaxants - baclofen and tizanidine.
• Substances affecting liver enzymes (particularly cytochrome P450).

Inhibitors (e.g., cimetidine, isoniazid, erythromycin, omeprazole, esomeprazole) reduce clearance and may potentiate the effects of benzodiazepines. Itraconazole, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the CYP3A4 isoenzyme of cytochrome P450 and may increase plasma levels of benzodiazepines. The effects of benzodiazepines may be enhanced and prolonged when used concomitantly. A reduction in benzodiazepine dose may be necessary.

Inducers (e.g., rifampicin) may increase the clearance of benzodiazepines.

• Antihypertensives, vasodilators, and diuretics:

Enhanced hypotensive effect of ACE inhibitors, alpha-blockers, angiotensin II receptor antagonists, calcium channel blockers, adrenergic neuron blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside, and diuretics.

Enhanced sedative effect with alpha-blockers or moxonidine.

• Dopaminergics: possible antagonism of levodopa effect.
• Antacids: concomitant use may delay absorption of lorazepam.
• Zidovudine: lorazepam increases the clearance of zidovudine.
• Contraceptives containing estrogens: possible inhibition of hepatic metabolism of lorazepam.
• Theophylline/aminophylline: enhances metabolism of lorazepam, possibly reducing its effect.
• Caffeine: concomitant use may lead to reduced sedative and anxiolytic effects of lorazepam.

Grapefruit juice: inhibition of CYP3A4 may increase plasma concentration of lorazepam (possible enhancement of sedation and amnesia). This interaction may be of minor significance in healthy individuals, but it is unclear whether other factors such as advanced age or hepatic cirrhosis increase the risk of adverse effects with concomitant use.

Special precautions for use.

Hypersensitivity reactions.

Severe anaphylactic/anaphylactoid reactions have been reported during benzodiazepine use. Cases of angioedema involving the tongue, glottis, or larynx have been reported in patients receiving the first or subsequent doses of benzodiazepines. Some patients taking benzodiazepines experienced additional symptoms such as dyspnea, throat tightness, nausea, and vomiting. Some patients required emergency medical treatment. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur, and these conditions may be life-threatening. Patients who have experienced angioedema after benzodiazepine treatment should not receive lorazepam again.

Lorazepam should be used with caution in patients with a history of allergic conditions. Patients with impaired respiratory function.

The use of benzodiazepines, including lorazepam, may cause potentially fatal respiratory depression. Therefore, lorazepam should be used with caution in patients with impaired respiratory function (e.g., COPD).

Concomitant use with opioids.

Concomitant use of lorazepam and opioids may result in profound sedation, respiratory depression, coma, and death. Therefore, it is generally inappropriate to co-prescribe opioids and sedative agents such as benzodiazepines or benzodiazepine-like drugs. If co-prescribing lorazepam with opioids is considered necessary, doses and duration of treatment should be limited to the minimum required (see recommendations in the section "Dosage and administration"). Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, it is strongly recommended that patients, and caregivers when appropriate, be informed about the need to monitor for these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Psychological and paradoxical reactions.

Paradoxical reactions have occasionally been reported during benzodiazepine use (see section "Adverse reactions"). Such reactions are particularly expected in children and elderly patients. If paradoxical reactions occur, treatment with lorazepam should be discontinued. Anxiety and tension caused by everyday stress usually do not require treatment with anxiolytics.

Patients with depression.

Depression may emerge or worsen during treatment with benzodiazepines, including lorazepam. Benzodiazepine use may unmask suicidal tendencies in patients with depression; therefore, they should not be used without adequate antidepressant therapy.

The possibility of suicide should be considered, and therefore lorazepam should not be prescribed in large quantities.

Lorazepam is not indicated for the treatment of endogenous depression or psychotic disorders, except in cases and as temporary, adjunctive medication in patients with associated anxiety or insomnia that are not adequately controlled by primary antidepressant or neuroleptic therapy.

Patients with circulatory disorders.

Enhanced drug response should be expected in patients with impaired cerebral circulation, which should be considered when selecting dosage. Although hypotension is rare, benzodiazepines should be used with caution in patients in whom a drop in blood pressure may lead to cardiovascular or cerebrovascular complications.

Seizures.

Benzodiazepines may provoke tonic-clonic seizures in patients with Lennox-Gastaut syndrome. This should be considered when using lorazepam.

Concomitant use with other sedative agents.

Patients should be informed that tolerance to other sedatives may be reduced, and such agents should either be discontinued or administered in lower doses when used concomitantly with lorazepam.

Elderly patients.

Reduced alertness and general weakness in elderly or debilitated patients (due to recent surgery or poor general condition) may persist for a prolonged period.

Lorazepam should be used with caution in elderly patients due to the risk of sedation and/or muscle weakness, which may increase the risk of falls with serious consequences in this patient group. Elderly or debilitated patients may be more sensitive to the effects of lorazepam; therefore, closer monitoring is required, and the dose should be reduced (see section "Special precautions for use").

Amnesia.

Benzodiazepines may cause anterograde amnesia, which typically occurs several hours after administration. To reduce the risk, patients should ensure uninterrupted sleep of 7–8 hours duration (see section "Adverse reactions").

Long-term use.

The need for continued lorazepam use should be regularly reviewed. During long-term benzodiazepine therapy, regular monitoring of blood parameters and liver function is recommended as a precautionary measure, since blood dyscrasias or elevated liver enzymes may occasionally occur (see section "Adverse reactions").

Patients with impaired liver function.

As with all benzodiazepines, lorazepam use may accelerate the development of hepatic encephalopathy. Therefore, lorazepam should be used with caution in patients with hepatic insufficiency and/or encephalopathy (severe liver impairment; see section "Special precautions for use").

Patients with gastrointestinal and cardiovascular disorders. In patients with concomitant gastrointestinal and cardiovascular diseases and associated anxiety, significant benefit from lorazepam in treating these underlying conditions has not been observed. Caution is recommended when using lorazepam for prolonged periods, as well as in elderly or debilitated patients. Regular upper gastrointestinal tract examinations should be performed to detect any disturbances.

Tolerance.

Tolerance to the sedative effects of benzodiazepines may develop. Drug dependence.

Benzodiazepine use may lead to physical and psychological dependence. The risk of dependence is low if dosage and duration of treatment are followed as instructed, but increases with higher doses, longer duration of use, and is further increased in patients with a history of alcohol or drug abuse or in patients with significant personality disorders. The potential for dependence is reduced when lorazepam is used at appropriate doses for short-term treatment.

Withdrawal symptoms.

Withdrawal symptoms, particularly severe ones, are more commonly observed in patients who have received high doses over a prolonged period. Withdrawal symptoms (e.g., rebound insomnia) may appear as early as one week after stopping the recommended dose of lorazepam. Abrupt discontinuation of lorazepam therapy should be avoided. To prevent withdrawal symptoms, the dose of lorazepam should be gradually reduced after long-term treatment. Patients should be advised to consult their physician before increasing the dose or abruptly stopping lorazepam. In general, benzodiazepines should be prescribed only for a short period (e.g., 2–4 weeks). Continuous long-term use is not recommended. Abrupt discontinuation or rapid dose reduction of lorazepam after prolonged use may cause withdrawal symptoms, which may be life-threatening. These may range from mild dysphoria and insomnia to a severe syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremor, and seizures. More serious signs and symptoms of acute withdrawal, including life-threatening reactions, have included fever, depression, hallucinations, mania, psychosis, seizures, and suicidal ideation.

Convulsions/seizure attacks may occur more frequently in patients with pre-existing seizure disorders or in patients taking other medications that lower the seizure threshold. Antidepressants.

Symptoms described include headache, anxiety, tension, restlessness, confusion, irritability, withdrawal phenomena, dysphoria, dizziness, depersonalization, derealization, hyperacusis, tinnitus, paresthesia and numbness of extremities, increased sensitivity to light, noise, and physical contact/perception, involuntary movements, nausea, anorexia, diarrhea, panic attacks, myalgia/muscle pain, agitation, palpitations, tachycardia, dizziness, hyperreflexia, transient memory loss, and hyperthermia. Abrupt discontinuation of benzodiazepines has led to withdrawal symptoms similar to those observed after barbiturate or alcohol withdrawal.

Rebound phenomenon, insomnia, and anxiety: a temporary syndrome leading to increased recurrence of symptoms that were the initial reason for benzodiazepine treatment, which may occur after discontinuation. This may be accompanied by other reactions such as mood swings, anxiety, or difficulty sleeping and restlessness. Since the risk of these symptoms increases after abrupt discontinuation, gradual dose reduction is recommended.

Substance abuse.

Lorazepam has potential for abuse, particularly in patients with a history of alcohol or drug abuse. Substance abuse is a known risk with benzodiazepines; therefore, patients should be under appropriate supervision during lorazepam treatment. Fatal outcomes associated with overdose have been reported when benzodiazepines were used with other CNS depressants, including opioids.

Benzodiazepines, alcohol, and/or illicit substances. These risks should be considered when prescribing or dispensing lorazepam. To reduce these risks, the lowest effective dose should be used, and patients should be informed about proper storage and disposal of unused medication to prevent theft (e.g., by friends or relatives).

Important information on excipients.

Lactose. If a patient has known intolerance to certain sugars, consultation with a physician is recommended before taking this medicinal product.

Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy. There are clear data on the risks to the fetus from benzodiazepine use. Lorazepam should not be taken during pregnancy. Analysis of human umbilical cord blood shows that benzodiazepines and their metabolites—glucuronides—cross the placental barrier. Women of reproductive age who are planning pregnancy or suspect they may be pregnant should inform their physician to determine whether therapy should be discontinued. Use of benzodiazepines in late pregnancy or during labor may result in withdrawal syndrome in the newborn. In infants whose mothers received benzodiazepines in late pregnancy or during labor, symptoms such as hypotonia, hypothermia, respiratory depression, apnea, decreased activity, feeding difficulties, or impaired sucking reflex, as well as metabolic disturbances in cold environments, have been observed.

Breastfeeding. Since benzodiazepines and their metabolites pass into breast milk, lorazepam is not recommended during breastfeeding. Sedation and weakened sucking reflex have been reported in infants whose mothers took benzodiazepines during breastfeeding. Infants whose mothers took benzodiazepines during breastfeeding should be monitored for pharmacological effects of benzodiazepines (e.g., sedation and irritability).

Fertility. Data on effects on fertility are lacking.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product has a marked effect on the ability to drive and operate machinery. This effect is intensified by alcohol.

Patients should be warned that sedation, amnesia, concentration disturbances, dizziness, blurred vision, and impaired muscle function may occur, and if these symptoms occur, they should not drive or operate machinery or engage in other similar activities. The likelihood of impaired vigilance may increase if sleep duration is insufficient. Concomitant use of medications may enhance these effects (see section "Interaction with other medicinal products and other forms of interaction").

Dosage and Administration

The dosage of the medicinal product should be adjusted according to individual patient needs. The lowest effective dose for the shortest possible duration of treatment should be prescribed. The risk of withdrawal syndrome and rebound syndrome is higher with abrupt discontinuation of therapy. Therefore, treatment should be discontinued gradually (see section "Special Warnings and Precautions for Use").

Adults.

Depending on the severity of symptoms and duration of treatment, the recommended dosage is:
For anxiety and anxiety states: 1–4 mg of lorazepam 2–3 times daily.
For sleep disturbances: 1–2 mg taken half an hour before bedtime.

For preoperative sedation: 2–4 mg of lorazepam before surgery and/or 1–2 hours prior to the procedure, and also 2–3 mg the night before surgery.

Elderly and debilitated patients.

For elderly and debilitated patients, the initial dose should be reduced by approximately 50%, and dosage adjusted according to clinical need and tolerability (see section "Special Warnings and Precautions for Use").

Renal or hepatic impairment.

Lower doses may be sufficient for these patients (see section "Special Warnings and Precautions for Use"). Use in patients with severe hepatic insufficiency is contraindicated (see section "Contraindications").

Pediatric population (from 6 years of age).

Premedication: 0.5–2.5 mg calculated at 0.05 mg/kg, rounded to the nearest 0.5 mg according to body weight, administered at least one hour before surgery.

Route of administration.

For oral use.

Important information during treatment:

• Treatment should be conducted under close medical supervision;
• At the lowest effective dose;
• For the shortest possible duration (not exceeding 4 weeks).

Dosages must be individualized. Clinical assessment of the patient should be performed regularly during treatment. Continuous or long-term use is not recommended (due to insufficient data on long-term safety and efficacy, and the potential risk of developing drug dependence – see section "Special Warnings and Precautions for Use").

At the beginning of treatment, the patient should be informed that:

• Treatment will be time-limited;
• Dosage will be gradually reduced;
• There is a possibility of rebound syndrome occurring.

Children.

Do not use in children under 6 years of age, as safety and efficacy have not been established in this age group.

Overdose.

In case of overdose, it should be considered that the patient may have taken multiple medicinal products simultaneously. As with other benzodiazepines, overdose is generally not life-threatening, except when lorazepam is taken concomitantly with other central nervous system (CNS) depressants (including alcohol).

Symptoms. Benzodiazepine overdose typically results in CNS depression, with symptoms ranging from drowsiness to coma, depending on severity. When lorazepam is taken alone, mild symptoms include sedation, confusion, paradoxical reactions, and lethargy. In severe cases, ataxia, decreased muscle tone, hypotonia, cardiovascular and respiratory depression may occur; coma is rare, and death following lorazepam overdose is very rare.

Treatment. Supportive care is primarily recommended until the drug is eliminated from the body. Vital signs and fluid balance should be closely monitored. Airway patency should be maintained, and artificial ventilation applied if necessary. In cases of benzodiazepine overdose, emesis should be induced if the patient is conscious. For unconscious patients, gastric lavage should be performed with appropriate airway protection. If gastric emptying is not feasible, activated charcoal should be administered to prevent further absorption of the drug. Induction of emesis is contraindicated if there is a risk of aspiration.

Lorazepam is poorly dialyzable.

To counteract the CNS effects of benzodiazepines in overdose, flumazenil (Anexate) may be used in intensive care settings (to restore spontaneous respiration and regain consciousness, thereby avoiding intubation; extubation may be performed if appropriate).

It should be noted that flumazenil acts as an antidote, not as a benzodiazepine substitute. When using flumazenil as an antidote, the high risk of seizures must be considered, particularly in patients with a history of long-term benzodiazepine therapy or concomitant use of tricyclic antidepressants.

For hypotension and respiratory depression, standard emergency supportive measures should be applied.

Adverse reactions.

Adverse reactions, if they occur, are usually observed at the beginning of therapy and typically decrease in severity or resolve with continued treatment or with dose reduction.

The most common adverse reactions associated with benzodiazepines include daytime drowsiness, dizziness, muscle weakness, and ataxia.

Adverse reactions are classified by frequency of occurrence as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).

System organ class	Frequency	Adverse reaction
Blood and lymphatic system	very rare	Thrombocytopenia, leukopenia, agranulocytosis, pancytopenia.
Immune system	very rare	Hypersensitivity, including anaphylactic/anaphylactoid reactions, angioedema.
Endocrine system	very rare	Inappropriate antidiuretic hormone secretion, hyponatremia.
Psychiatric	rare	Confusion, depression and worsening of depression, blunting of emotions, disinhibition, euphoria, appetite changes, sleep disturbances, libido disorder, decreased orgasm sensation.
	unknown	Drug dependence, suicidal thoughts/attempts. Paradoxical reactions such as restlessness, excitement, irritability, aggression, rage, nightmares, hallucinations, psychoses, sexual excitement, and inappropriate behavior have been reported occasionally during use.
Nervous system	very common	Drowsiness (during daytime), sedation.
	common	Dizziness, ataxia.
	rare	Headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment.
	very rare	Tremor, extrapyramidal disorders, coma (see section "Overdose").
Eye disorders	rare	Visual disturbances (diplopia, blurred vision).
Vascular disorders	rare	Hypotension (see section "Special precautions for use").
Respiratory, thoracic and mediastinal disorders	rare	Apnea, exacerbation of apnea, exacerbation of obstructive lung disease. Respiratory depression (see section "Overdose"). The severity of these symptoms is dose-dependent.
Gastrointestinal disorders	rare	Nausea, constipation, salivation.
Hepatobiliary disorders	rare	Liver function test abnormalities (increased blood bilirubin, increased transaminases, increased alkaline phosphatase), jaundice.
Skin and subcutaneous tissue disorders	rare	Rash, allergic dermatitis, alopecia.
Musculoskeletal and connective tissue disorders	common	Muscle weakness.
Reproductive system and breast disorders	rare	Impotence.
General disorders and administration site conditions	common	Asthenia, fatigue.
	unknown	Hypothermia.
General disorders and administration site conditions	unknown	Falls.

Withdrawal symptoms (see section "Special precautions for use").

Symptoms reported after discontinuation of benzodiazepines include headache, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating, and rebound syndrome, in which symptoms that led to benzodiazepine treatment recur in an intensified form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

In severe cases, the following symptoms may occur: derealization; depersonalization; hyperacusis; tinnitus; numbness and tingling of extremities; increased sensitivity to light, noise, and physical contact; involuntary movements; hyperreflexia, tremor, nausea, vomiting; diarrhea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, transient memory loss, hallucinations/delirium; catatonia; hyperthermia, seizures. Seizures may be more common in patients with pre-existing seizure disorders or in those taking other medicinal products that lower the seizure threshold, such as antidepressants.

Reporting of suspected adverse reactions.

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical personnel, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging to protect from light at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

Tablets of 0.5 mg – 10 tablets per blister; 1 or 2 blisters per cardboard box. Tablets of 1 mg – 10 tablets per blister; 1 or 2 blisters per cardboard box. Tablets of 2.5 mg – 10 tablets per blister; 1 or 2 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Tarchomin Pharmaceutical Works "Polfa" S.A.

Manufacturer's address and place of business.

Aleksandra Fleminga Street 2, Warsaw, 03-176, Poland.