Lorazepam-zn

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

Composition:

Active substance: lorazepam;

1 tablet contains 1 mg or 2.5 mg of lorazepam;

Excipients: lactose monohydrate; microcrystalline cellulose; magnesium stearate; potassium polycriline.

Pharmaceutical form. Tablets.

Main physicochemical properties: almost white, round cylindrical tablets with flat surfaces, bevelled edges, and a score line on one side.

Pharmacotherapeutic group.

Medicinal products for the 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, exhibiting therapeutic effects even at low doses.

Lorazepam demonstrates pronounced anxiolytic and, at higher doses, anticonvulsant effects, while its sedative and, especially, muscle relaxant effects are relatively weak.

By reducing emotional factors, lorazepam eliminates conditions conducive to the development of diseases caused by emotional and psychoreactive factors.

When taken once at night, the drug produces a hypnotic effect.

The pharmacological action of benzodiazepine drugs is due to their high affinity for receptors of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Benzodiazepines enhance the effects of GABA, leading to the opening of chloride channels in cell membranes and potentiation of 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 in blood is about 90%.

The volume of distribution of protein-bound lorazepam ranges from 0.3 to 1.3 L/kg; for unbound lorazepam, it 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 small amounts.

Metabolism

Lorazepam is inactivated by more than 90% through 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

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

Pharmacokinetics in specific patient populations

Pharmacokinetics in elderly individuals: studies involving elderly and younger patients have demonstrated age-dependent differences in lorazepam pharmacokinetics.

Elimination in hepatic impairment: no changes in pharmacokinetic parameters were observed in patients with liver disease (e.g., hepatitis, alcoholic cirrhosis).

Elimination in renal impairment: in patients with renal insufficiency, metabolic clearance of lorazepam and plasma concentrations of unbound lorazepam remain within normal limits.

However, a prolonged elimination half-life of lorazepam glucuronide is observed, and this inactive metabolite may accumulate.

Following subchronic dosing, elimination of unbound lorazepam is also altered.

Clinical characteristics.

Indications.

Lorazepam-ZN is used only if symptoms are clinically significant or if they limit the patient in daily life.

Insomnia or anxiety disorders may be symptoms of physical or mental illnesses; therefore, in the presence of sleep disturbances or anxiety disorders, the underlying disease causing such symptoms should be diagnosed, if possible, and treated accordingly.

Lorazepam has proven therapeutic efficacy in most conditions where anxiety plays a significant role.

Symptomatic treatment of anxiety disorders, tension states, and excited states as a complicating factor in organic diseases (e.g., gastrointestinal dysfunction – see "Special precautions").

Adjunctive therapy for anxiety disorders in depression and schizophrenia.

Short-term treatment of anxiety and sleep disturbances caused by stress.

Sedation prior to diagnostic and surgical procedures.

Contraindications.

• Hypersensitivity to benzodiazepines and/or other components of the medicinal product;
• Myasthenia gravis (myasthenia gravis);
• Severe respiratory insufficiency;
• Sleep apnea syndrome;
• Severe hepatic or renal insufficiency;
• Shock, coma, collapse;
• Drug, alcohol, or narcotic dependence;
• Acute intoxication with alcohol, hypnotics, analgesics, and psychotropic agents;
• Pediatric age under 12 years.

Interaction with other medicinal products and other forms of interaction.

Opioids
Concomitant use of benzodiazepines with opioids increases the risk of sedation, respiratory depression, coma, and fatal outcome due to mutual potentiation of central nervous system (CNS) depression. Both the doses and duration of concomitant use of benzodiazepines and opioids should be limited.

Enhanced CNS depression with increased risk of potentially fatal respiratory depression may occur when lorazepam is taken concomitantly with other CNS depressants, such as antipsychotics (neuroleptics, e.g., clozapine), hypnotics, barbiturates, anxiolytics/sedatives, antidepressants, antiepileptics, analgesics, anesthetics, and antihistamines with sedative effects.

Alcohol consumption should be avoided during treatment. Concomitant use of the medicinal product with alcohol results in enhanced sedative effects.

Concomitant use with analgesics (particularly opioids) may enhance euphoria, potentially increasing the risk of psychological dependence.

Benzodiazepines may potentiate the effects of muscle relaxants.

Concomitant administration of clozapine and lorazepam may lead to marked sedation, hypersalivation, and ataxia.

Concomitant use of lorazepam with valproate may increase plasma concentrations of lorazepam and reduce lorazepam clearance. In such cases, the dose of lorazepam should be halved.

Concomitant use of lorazepam and probenecid leads to faster onset or prolonged effect of lorazepam due to increased elimination half-life and reduced total clearance of lorazepam. In such cases, the dose of lorazepam should be halved.

Additional administration of theophylline/aminophylline may reduce the effect of benzodiazepines, including lorazepam.

Lorazepam does not affect the cytochrome P450 enzyme system activity. Therefore, no interactions occur with drugs metabolized by this enzyme.

Special precautions for use.

Risks of concomitant use of opioids and benzodiazepines

Concomitant use of benzodiazepines and opioids may result in sedation, respiratory depression, coma, and fatal outcomes. Due to these risks, concomitant use of opioids and benzodiazepines should be reserved for patients for whom no alternative treatment options are appropriate. If a decision is made to use lorazepam and opioids together, the lowest effective dose and shortest possible duration of concomitant treatment should be prescribed. Patients must be closely monitored for signs and symptoms of respiratory depression and sedation.

Lorazepam is not intended for primary therapy of endogenous depressions and psychotic disorders and should not be used as monotherapy in patients suffering from depression. However, if primary treatment with antidepressants or neuroleptics does not provide adequate control of anxiety or insomnia, temporary use of lorazepam as an adjunctive agent is permitted (see section "Interaction with other medicinal products and other forms of interaction"). In depressive anxiety disorders, the possibility of suicide attempts should be considered; therefore, lorazepam should not be prescribed in high doses.

Anxiety states and tension caused by everyday stress generally do not require treatment with anxiolytics.

Like other drugs that suppress CNS function, benzodiazepines may lead to encephalopathy in patients with severe hepatic insufficiency.

Like other benzodiazepines, lorazepam may cause life-threatening respiratory depression; therefore, lorazepam should be used with particular caution in patients with respiratory impairment (e.g., chronic obstructive pulmonary disease).

Severe anaphylactic/anaphylactoid reactions have been reported during benzodiazepine therapy. Cases of angioedema involving the tongue, glottis, or larynx have been reported after administration of the first or subsequent doses of benzodiazepines. In some patients, additional symptoms such as dyspnea, laryngeal edema, nausea, and vomiting have been observed. Some patients required emergency medical intervention. Angioedema involving the tongue, glottis, or larynx may cause airway obstruction and lead to death. Patients who develop angioedema during benzodiazepine therapy should avoid re-exposure to the drug.

Paradoxical reactions have occasionally been reported with benzodiazepine use, primarily in elderly and geriatric patients. If such reactions occur, the drug should be discontinued (see section "Side effects").

Lorazepam should be used cautiously in elderly patients due to the potential for sedation and/or muscle weakness, which may increase the risk of falls with serious consequences. Elderly patients should receive reduced doses (see section "Dosage and administration").

Lorazepam should generally not be used, or used only in low doses, in patients with cerebral sclerosis or those with weakened general health.

The drug should be used with caution in elderly and geriatric patients with chronic respiratory insufficiency, liver or kidney disease.

Although hypotension has been very rarely observed as an adverse effect, the drug should be used cautiously in patients in whom a drop in blood pressure may lead to cardiovascular or cerebrovascular complications. This is particularly relevant for elderly and geriatric patients.

If long-term therapy with lorazepam is medically necessary, regular monitoring of blood counts and liver function tests is recommended.

Close medical supervision is required for patients predisposed to dependence, such as those with alcohol or drug addiction.

Reduced alertness may persist for prolonged periods, for example, in elderly and geriatric patients, in those with weakened general health, when lorazepam is used concomitantly with other drugs, or as a result of postoperative weakness.

The drug should be used cautiously in the treatment of patients with closed-angle glaucoma.

Dependence

Benzodiazepine use may lead to psychological or physical dependence. This risk increases with prolonged use, high doses, and in patients with predisposing factors, such as those with alcohol or drug dependence, or clinically relevant personality disorders. The likelihood of dependence can be reduced by prescribing appropriate dosing regimens and limiting treatment duration.

Withdrawal syndrome primarily occurs after abrupt discontinuation of therapy and includes symptoms such as tremor, restlessness, sleep disturbances, confusion, dizziness, irritability, depression, anxiety, headache, tension, rebound syndrome, dysphoria, depersonalization, personality disturbances, hyperacusis, tingling and numbness in the extremities, increased sensitivity to light and sound, sensory disturbances, involuntary movements, short-term memory loss, reduced concentration, and hyperthermia. Additional symptoms may include sweating, nausea, vomiting, diarrhea, loss of appetite, palpitations, tachycardia, hyperreflexia, abdominal cramps, muscle spasms, perceptual disturbances, and, rarely, delirium, hallucinations, panic attacks, and cerebrospinal seizures or convulsions. Seizures and convulsions are more commonly observed in patients with pre-existing seizure disorders or those taking other drugs that lower the seizure threshold (e.g., antidepressants).

The onset of withdrawal syndrome depends on the duration of action of the substance and may range from several hours to several weeks or more after discontinuation of therapy.

To minimize the risk of dependence, benzodiazepines should be used only after careful evaluation of the indication and for the shortest possible duration (e.g., as a hypnotic—no longer than four weeks). Prolonged use of lorazepam is not recommended. The need for continued treatment should be reviewed periodically. Long-term therapy should be reserved for specific patient groups (e.g., panic attacks), although the benefit-risk ratio of such therapy has not been sufficiently studied.

To prevent withdrawal syndrome, gradual discontinuation of the drug is recommended in each case, with stepwise dose reduction of lorazepam. If withdrawal symptoms occur, frequent and careful medical monitoring and patient support are advised.

There is evidence that tolerance to benzodiazepines may develop during therapy.

The potential for lorazepam dependence is higher in patients with alcohol or drug dependence.

Amnesia, psychiatric, and "paradoxical" reactions: see section "Side effects".

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

Use during pregnancy or breastfeeding

There are clear data on the risks to the fetus associated with 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.

Use of benzodiazepines in late pregnancy or during labor may lead to withdrawal syndrome in the newborn. Infants born to mothers who received benzodiazepines in late pregnancy or during labor have shown symptoms such as hypotonia, hypothermia, respiratory depression, apnea, reduced activity, feeding difficulties, impaired sucking reflex, and metabolic disturbances in cold environments.

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.

Since benzodiazepines and their metabolites are excreted in breast milk, lorazepam is not recommended during breastfeeding. Cases of drowsiness and weakened sucking reflex have been reported in infants whose mothers used benzodiazepines during lactation. Infants whose mothers used benzodiazepines during breastfeeding should be monitored for pharmacological effects of benzodiazepines (e.g., sedation and irritability).

Ability to affect reaction speed when driving or operating machinery

Lorazepam may significantly impair reaction speed when driving or operating machinery. This effect is intensified by alcohol consumption.

As with other CNS depressants, patients prescribed lorazepam should refrain from driving or operating hazardous machinery until it is established that the drug does not cause drowsiness or dizziness.

Dosage and Administration

The dosage of the medicinal product should be individually adjusted according to the patient's needs.

The lowest therapeutic dose and the shortest 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 Instructions").

Depending on the severity of symptoms and duration of treatment, the recommended dose is 1 mg of lorazepam 2–3 times daily.

For sleep disturbances, administration of 1 mg of lorazepam 30 minutes before bedtime is generally sufficient.

In psychiatric practice: administer 3–7.5 mg of lorazepam daily, divided into 3–4 doses.

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

Elderly and debilitated patients.

For elderly and debilitated patients, the initial dose should be reduced by approximately 50%, and dosage should be adjusted according to necessity and tolerability (see section "Special Instructions").

Children.

Do not use in children under 12 years of age, as safety and efficacy have not been established in this age group.

Overdose.

In cases of overdose, consider the possibility that the patient may have taken multiple drugs simultaneously.

As with other benzodiazepines, overdose is generally not life-threatening unless lorazepam is taken concomitantly with other central nervous system (CNS) depressants (including alcohol).

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 drowsiness, confusion, paradoxical reactions, and lethargy. In severe cases, ataxia, decreased muscle tone, hypotension, cardiovascular and respiratory depression may occur; coma is rare, and fatal outcomes following lorazepam ingestion are very rare.

In overdose, supportive therapy should be primarily maintained 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 should be applied if necessary.

In case of benzodiazepine overdose, induce vomiting only if the patient is conscious. For unconscious patients, gastric lavage should be performed with appropriate airway protection. If gastric emptying is not feasible, administer activated charcoal to prevent further drug absorption.

Inducing vomiting is contraindicated if there is a risk of aspiration.

Lorazepam is poorly dialyzable.

To counteract the effects of benzodiazepines on the CNS in overdose, flumazenil (Anexate) may be used in intensive care settings (to restore spontaneous respiration and achieve consciousness, thereby avoiding intubation, or allowing for extubation).

Note 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 prolonged benzodiazepine therapy or concomitant use of tricyclic antidepressants.

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

Adverse reactions

Adverse reactions are categorized by frequency of occurrence as follows:

Very rare: < 0.01 %;
Rare: ≥ 0.01 % – < 0.1 %;
Occasional: ≥ 0.1 % – < 1 %;
Frequent: ≥ 1 % – < 10 %;
Very frequent: ≥ 10 %;
Frequency not known: cannot be estimated from available data.

Blood and lymphatic system disorders:
Frequency not known – thrombocytopenia, agranulocytosis, pancytopenia.

Immune system disorders:
Frequency not known – hypersensitivity reactions, anaphylactic/anaphylactoid reactions, angioneurotic edema.

Metabolism and nutrition disorders:
Frequency not known – syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia.

Psychiatric disorders:
Following administration of benzodiazepines and benzodiazepine-like substances, the following reactions have been observed: restlessness, excitement, anxiety, hostility, anger, rage, irritability, aggression, delirium, mania, nightmares, hallucinations, psychosis, abnormal behavior, and other undesirable behavioral effects.

Depressive symptoms may occur during benzodiazepine therapy.

Nervous system disorders:
Very frequent – sedation, fatigue, somnolence.
Frequent – ataxia, confusion, depression, marked depression, dysphoria.
Occasional – libido changes, impotence, anorgasmia.
Frequency not known – extrapyramidal symptoms, tremor, dizziness, visual disturbances (diplopia, blurred vision), dysarthria/incomprehensible speech, headache, seizures/convulsions, amnesia, disinhibition, coma, suicidal thoughts/attempts, concentration impairment, loss of balance.

Transient anterograde amnesia or memory impairment has been reported with benzodiazepine use. Such adverse reactions mainly occurred with high doses of lorazepam and, in certain cases, were considered desirable (see "Indications").

Cardiac disorders:
Frequency not known – hypotension, decreased arterial pressure.

Respiratory, thoracic and mediastinal disorders:
Frequency not known – respiratory depression, apnea, exacerbation of sleep apnea, exacerbation of obstructive lung disease. The severity of these symptoms is dose-dependent.

Gastrointestinal disorders:
Occasional – nausea.
Frequency not known – constipation.

Hepatobiliary disorders:
Frequency not known – increased bilirubin levels, jaundice, increased transaminase and alkaline phosphatase levels.

Skin and subcutaneous tissue disorders:
Frequency not known – allergic reactions, alopecia.

General disorders and administration site conditions:
Frequent – muscle weakness, asthenia.
Frequency not known – hypothermia.

Reporting of adverse reactions

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

Shelf life. 2 years.

Storage conditions.

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

Packaging.

1 mg tablets – 10 tablets per blister; 1, 2, 3 or 5 blisters per cardboard box;
2.5 mg tablets – 10 tablets per blister; 1, 2, 3 or 5 blisters per cardboard box.

Prescription category.

Prescription only.

Manufacturer.

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

Manufacturer's address and location of operations.

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