Lorazepam-zn

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

Composition:

Active ingredient: lorazepam;

1 ml of solution contains 2 mg of lorazepam;

Excipients: benzyl alcohol, polyethylene glycol 400, propylene glycol.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear, colorless or almost colorless viscous liquid.

Pharmacotherapeutic group.

Medicinal products for the treatment of the nervous system. Psycholeptics. Anxiolytics. Benzodiazepine derivatives. Lorazepam. ATC code N05B A06.

Pharmacological properties

Pharmacodynamics

Lorazepam is a psychotropic substance belonging to the class of 1,4-benzodiazepine derivatives, which relieves tension, agitation, and anxiety, and also has sedative and hypnotic effects. In addition, lorazepam reduces muscle tone and has anticonvulsant activity.

Lorazepam has very high affinity for receptors at specific binding sites within the central nervous system (CNS). These benzodiazepine receptors are closely functionally linked to receptors of the inhibitory neurotransmitter—gamma-aminobutyric acid (GABA). After binding to benzodiazepine receptors, lorazepam enhances GABAergic neurotransmission.

Pharmacokinetics

Absorption

After intravenous administration, maximum plasma concentrations exceeding 30 mg/mL per 1 mg of administered lorazepam are observed immediately following injection. The onset of action typically occurs within 0.5–5 minutes after administration.

Protein binding

Lorazepam is bound to plasma proteins, primarily albumin, within the range of 80.4–93.2%, which is slightly higher than the 65–70% reported for its main metabolite, lorazepam glucuronide.

Penetration into the CNS

Concentrations of lorazepam and its metabolites detected in cerebrospinal fluid are considerably lower than plasma concentrations at the same time point (on average less than 5% of the corresponding plasma concentration).

Ability to cross the placental barrier

Lorazepam and lorazepam glucuronide cross the placental barrier and reach fetal blood and amniotic fluid. Neither lorazepam nor its glucuronide accumulates in the fetus. Neonatal organisms deactivate lorazepam via glucuronidation, although at a slower rate than in the mother.

Excretion into breast milk

Lorazepam and its glucuronide pass into breast milk in negligible concentrations. The maximum recorded concentration in maternal serum was approximately 13% for lorazepam and approximately 20% for the glucuronide, corresponding to 2.4 µg of lorazepam and 7 µg of lorazepam glucuronide per liter of breast milk for each 1 mg dose received by the mother.

Biotransformation

The main metabolite of lorazepam, which undergoes nearly complete biotransformation, is the glucuronide conjugate. This metabolite has shown virtually no pharmacological activity in animal studies. No active metabolites are formed.

Elimination

Various studies have shown that the elimination half-life of lorazepam is 12–16 hours, regardless of the route of administration. The elimination half-life of the glucuronide metabolite ranges from 12.9 to 16.2 hours.

In neonates, the elimination half-life may be 2 to 4 times longer than in the mother. Except during the first days of life, no age-dependent changes in terminal half-life have been observed.

Elimination in renal impairment

In cases of renal insufficiency, metabolic inactivation and the elimination half-life of lorazepam remain unchanged; however, elimination of the pharmacodynamically inactivated glucuronide metabolite is significantly delayed.

Dialyzability and behavior during forced diuresis, e.g., in cases of intoxication

In renal impairment, lorazepam clearance remains normal, but accumulation of the pharmacodynamically inactivated lorazepam glucuronide occurs. During a 6-hour hemodialysis session, only 8% of the unbound drug and 40% of the glucuronide were removed. Therefore, hemodialysis has limited utility in cases of severe intoxication. The same applies to forced diuresis.

Elimination in hepatic impairment

No significant changes in lorazepam clearance have been observed in patients with liver disease (e.g., hepatitis, cirrhosis). Glucuronidation is likely not substantially impaired in liver disease. However, severe hepatic dysfunction may lead to a prolonged terminal elimination half-life.

Clinical characteristics.

Indications.

• For sedation (superficial sedation) before and during surgical and diagnostic procedures, aimed at reducing fear, tension, and ensuring that the patient retains no memory of the procedure.
• Initial treatment of severe neurotic symptoms of anxiety depression and pronounced phobias.
• Short-term adjunctive therapy for severe anxiety states and excited states in psychosis and depression, when primary therapy with CNS depressants and/or antidepressants does not control or inadequately controls such symptoms.
• Treatment of epileptic status (Status epilepticus) associated with various focal or generalized seizures. Lorazepam administration is recommended for: generalized (tonic-clonic) seizures, generalized stupor (ptomaine), or so-called "spike-wave stupor" states, focal motor or psychomotor seizures, as well as combined conditions such as generalized seizures with focal onset. Primary therapy with the drug promotes prolonged suppression of seizure activity.
• Lorazepam is not intended for long-term treatment of epilepsy. After seizure termination, other agents should be used to prevent further seizures. In the treatment of epileptic status (Status epilepticus) associated with acute reversible metabolic disturbances (e.g., hypoglycemia, hypocalcemia, hyponatremia, etc.), the specific disturbance must be urgently corrected.

Contraindications.

Lorazepam is not recommended for use in cases of hypersensitivity to the active substance, other benzodiazepines, or excipients, as well as in shock or collapse.

Lorazepam must not be used concomitantly with scopolamine, as this combination leads to enhanced sedative effects, hallucinations, and irrational behavior.

Due to the presence of benzyl alcohol, the drug must not be administered to newborns and infants (see section "Special instructions").

Interaction with other medicinal products and other types of interactions.

When lorazepam is taken together with other medicinal products that depress CNS function (e.g., neuroleptics, tranquilizers, antidepressants, hypnotics/sedatives, anesthetics, beta-blockers, opioid analgesics, sedative antihistamines, antiepileptics) or alcohol, an enhanced CNS depressant effect is observed. Concomitant use of the drug with alcohol is not recommended.

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

The effects of muscle relaxants and analgesics may be enhanced.

Concomitant administration of the drug with scopolamine often leads to hallucinations, irrational behavior, and profound sedation. Therefore, their simultaneous use is not recommended (see section "Contraindications").

In individual cases, concomitant administration of lorazepam and clozapine has been associated with pronounced depression, vascular collapse, respiratory arrest, hypersalivation, and impaired motor coordination.

There have been reports of apnea, coma, bradycardia, cardiac arrest, and fatal outcomes, primarily among critically ill patients receiving lorazepam together with haloperidol.

Concomitant administration of lorazepam and valproic acid may lead to increased plasma concentration of lorazepam and reduced lorazepam clearance. When valproic acid is used concomitantly, the lorazepam dose should be reduced by approximately 50%.

Concomitant use of lorazepam and probenecid may result in a faster onset of action or prolonged effect of lorazepam due to an extended elimination half-life and reduced total clearance. When probenecid is used concomitantly, the lorazepam dose should be reduced by approximately 50%.

The use of theophylline or aminophylline may reduce the sedative effect of benzodiazepines, including lorazepam.

Lorazepam has no effect on oxidative metabolism activity (cytochrome P450 system). Therefore, interactions based on enzyme-induced effects on this system (e.g., cimetidine) are not expected.

Special precautions for use.

Risks of concomitant use of opioids and benzodiazepines

Concomitant administration 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 co-administer lorazepam and opioids, the lowest effective dose and shortest possible duration of concomitant treatment should be used. Close monitoring for signs and symptoms of respiratory depression and sedation is required in patients.

Avoid intra-arterial injection of lorazepam, as it may lead to arterial spasm, which in turn may cause cessation of blood supply to the arterial territory. Under certain conditions, this may result in gangrene and necessitate amputation.

Lorazepam should be used with particular caution in patients with myasthenia gravis, spinal and cerebellar ataxias, acute alcohol intoxication, or intoxication with drugs that depress CNS function (e.g., hypnotics or analgesics, neuroleptics, antidepressants, lithium), in sleep apnea syndrome, and in severe respiratory insufficiency.

As with any premedication, this drug should be used cautiously in elderly patients and in patients with severe diseases, those with limited respiratory reserve, and those with impaired central regulation mechanisms of respiration and cardiovascular function, due to the risk of cardiac or respiratory arrest.

The drug should also be used with caution in patients with alcohol, drug, or medication dependence, as well as in individuals predisposed to such dependence. Benzodiazepine drugs may lead to dependence with prolonged use. Lorazepam is not recommended for patients with renal insufficiency or significant hepatic impairment.

Lorazepam is not intended for primary therapy of endogenous depressions and psychosomatic disorders. However, if the main treatment with antidepressants or neuroleptics does not adequately control accompanying anxiety states or sleep disturbances, temporary use of tranquilizers such as lorazepam may be considered as adjunctive therapy. The drug should be used cautiously in patients with depressive disorders, as depressive symptoms may be exacerbated in some cases if not concurrently treated with antidepressants.

Benzodiazepine drugs may provoke tonic-clonic seizures in patients suffering from Lennox-Gastaut syndrome. This should be taken into account when treating such patients with lorazepam.

Cases of propylene glycol toxicity (e.g., lactic acidosis, hyperosmolality, hypotension) and polyethylene glycol toxicity (e.g., acute tubular necrosis) have been reported with high-dose administration of the drug. Patients at risk of propylene glycol accumulation and sensitive to its potential adverse effects include those with limited activity of alcohol- and aldehyde-degrading dehydrogenase enzymes, including children under 4 years of age, pregnant women, patients with severe renal or hepatic disease, and patients receiving treatment with disulfiram or metronidazole.

Use of the drug in deeply sedated patients, particularly under anesthesia, patients with obstructive lung disease, and elderly or debilitated patients may lead to respiratory impairment. Therefore, instruments for airway management should be prepared to support respiration.

Lorazepam should be administered with special caution to patients with status epilepticus, especially after administration of another CNS depressant drug or in severely ill patients. Consideration must be given to the possibility of respiratory arrest or partial airway obstruction. Equipment for respiratory support and resuscitation measures should be readily available.

Patients discharged home on the day of lorazepam administration must be accompanied.

Patients who have received lorazepam must remain under supervision for 24 hours after injection.

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

Since changes in blood parameters or elevated levels of liver enzymes in plasma have been observed in some cases during benzodiazepine use, periodic monitoring of blood counts and liver function markers is recommended with repeated administration of lorazepam.

Paradoxical reactions have been reported with benzodiazepine drugs (see section "Adverse reactions"). Such reactions may be expected in children and elderly patients. If paradoxical reactions occur, lorazepam therapy should be discontinued.

Respiratory depression, potentially leading to fatal outcomes, may occur during treatment with benzodiazepine drugs, including lorazepam.

Severe anaphylactic/anaphylactoid reactions have been reported during treatment with benzodiazepines. Cases of angioedema involving the tongue, glottis, or pharynx have been reported after the first or subsequent doses of benzodiazepines, which may lead to airway obstruction and fatal outcomes. In some patients, additional symptoms such as dyspnea, pharyngeal swelling, nausea, and vomiting have been observed. Some patients required emergency medical intervention. Re-administration of benzodiazepines should be avoided in patients who have experienced angioedema during benzodiazepine therapy.

Renal function monitoring is recommended during prolonged use.

Do not use in premature infants and newborns, as the product contains benzyl alcohol, which may cause toxic and allergic reactions in infants and children under 3 years of age.

Use during pregnancy or breastfeeding.

Pregnancy

The drug should be used during pregnancy only in exceptional cases and when strictly indicated, as there is currently insufficient therapeutic experience with lorazepam during this period. Due to the lack of sufficient experience with lorazepam in obstetrics, its use in such cases is not recommended.

The preservative benzyl alcohol contained in the drug may cross the placenta and cause severe adverse effects in newborns.

Prolonged use or high-dose administration should be avoided. Prolonged use of lorazepam during pregnancy may lead to withdrawal syndrome in newborns. Administration of high doses immediately before or during delivery may result in reduced activity, hypothermia, hypotonia, mild respiratory depression, and weakened sucking reflex (so-called "floppy infant syndrome") in newborns.

Previous human observations have not provided definitive data on teratogenic effects of therapeutic doses. However, based on experience with other benzodiazepines, a potential effect of lorazepam on fetal development cannot be excluded. Case histories report developmental abnormalities and delayed mental development in children exposed to the drug prenatally, following overdose or poisoning.

Period of breastfeeding

Lorazepam should not be used during breastfeeding. The drug passes into breast milk in small amounts (see section "Pharmacokinetics"). In cases of urgent need, a decision on discontinuation of breastfeeding should be made based on the circumstances of the individual case, including dosage.

Ability to affect reaction speed when driving or operating machinery.

This medicinal product, even when taken as prescribed, may alter reaction speed, significantly affecting the ability to participate actively in road traffic or to operate machinery. This is largely related to the effect of benzyl alcohol.

Patients who have received lorazepam should not drive vehicles, operate hazardous machinery, or engage in any activity requiring a high degree of attention within the next 24–48 hours. Reduced attention, for example in elderly patients due to postoperative weakness or poor general condition, may persist for a prolonged period.

Administration and Dosage

Use only under hospital conditions.

Single and daily dose

Premedication

The dose is determined by body weight to achieve optimal effect. Route of administration: intravenous.

0.044 mg per kg of body weight 15–20 minutes before surgery to achieve amnesia.

This dose is sufficient for many adults and should not be exceeded in patients aged 50 years and older; for such patients, an initial dose of 2 mg is usually adequate. For patients in whom amnesia regarding perioperative events is particularly desirable, a dose of 0.05 mg/kg body weight may be administered, with a maximum total dose of 4 mg.

Prior to intravenous injection, equipment for airway management must be prepared.

For elderly, debilitated patients, and those with severe respiratory or cardiovascular disorders, the dose should be lower than usual.

For patients with mild or moderate hepatic or renal impairment, the lowest effective dose should be selected, as prolonged drug action may be expected in such cases.

Doses of other agents capable of depressing CNS function should generally be reduced.

It is recommended to administer each subsequent drug with a separate syringe.

Psychiatric disorders

For acute anxiety states with or without psychomotor agitation – 0.05 mg per kg of body weight as the initial dose. If necessary, repeat the same dose after 2 hours.

Status epilepticus

The usual initial dose for patients aged 18 years and older is 4 mg of lorazepam administered slowly (2 mg/min). If seizures do not stop or recur within the next 10–15 minutes, the same dose may be repeated. If this repeated dose does not lead to improvement within the following 10–15 minutes, alternative measures for managing status epilepticus must be implemented. The maximum dose of lorazepam administered within 12 hours is 8 mg.

The initial dose for children aged 1 year and older and adolescents is 0.05 mg/kg body weight; if seizures persist or recur within the next 10–15 minutes, an additional dose of 0.05 mg/kg may be administered.

Administration method

Lorazepam may be used concomitantly with narcotic analgesics, other injectable analgesics, standard anesthetic agents, muscle relaxants, and atropine sulfate, but must not be used simultaneously with scopolamine.

2 mg of the drug must be diluted with physiological saline or water for injection in a 1:1 ratio before use. After dilution, administer slowly into a vein or into an infusion line; avoid accidental intraarterial injection (see section "Special precautions"). The injection rate should not exceed 2 mg of lorazepam per minute; injection should be controlled by repeated aspiration.

As usual, the solution for injection should be visually inspected prior to use for particulate matter, precipitate, or discoloration. Do not use solutions that have changed color or contain precipitate.

The following diluents are fully compatible with the drug for at least 1 hour: water for injection, physiological saline, 5% glucose solution.

Dilution recommendations

Draw the required volume of injection solution from the ampoule into a syringe, then add the required volume of diluent. Then pull back the syringe plunger and gently tilt the syringe forward and backward until the solution becomes homogeneous. Do not shake vigorously, as this may cause air bubbles in the injection solution.

If multiple or repeated use of the drug is indicated, the duration of treatment is determined by the physician.

Elderly and debilitated patients

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

Children

Treatment with lorazepam is contraindicated in children and adolescents under 18 years of age, except in cases of status epilepticus (see section "Administration and dosage"). Use in neonates and infants (children under 1 year of age) is contraindicated (see section "Contraindications").

Seizures and myoclonus have been observed in breastfed infants after maternal lorazepam administration.

Increased sensitivity to benzyl alcohol, polyethylene glycol, and propylene glycol in the drug formulation may occur in children. In neonates and children under 3 years of age, benzyl alcohol may cause toxic and anaphylactic reactions. After administration of solutions containing benzyl alcohol as a preservative, neonates have shown CNS depression, metabolic acidosis, gasping respiration, and high blood and urinary levels of benzyl alcohol and its metabolites (so-called "gasping syndrome"). Additional symptoms may include progressive neurological deterioration, seizures, intracranial hemorrhage, hematological abnormalities, skin necrosis, hepatic and renal failure, hypotension, bradycardia, and vascular collapse. CNS symptoms (e.g., seizures, ventricular hemorrhage), as well as unresponsiveness, tachypnea, tachycardia, and increased sweating, are associated with propylene glycol toxicity. Although standard therapeutic doses of the drug contain these substances in very small amounts, children receiving high doses may be more susceptible to the effects of these components under certain conditions.

Overdose

When evaluating each case of intoxication, it must be considered that the patient may have taken multiple drugs.

Symptoms of intoxication

Overdose of benzodiazepines usually manifests as CNS depression of varying severity, ranging from drowsiness to coma. Mild overdose symptoms may include drowsiness, confusion, somnolence, lethargy, ataxia, dysarthria, myalgia, and decreased arterial blood pressure. In cases of severe intoxication, central respiratory and circulatory depression and loss of consciousness may occur (intensive monitoring required!).

When combined with other CNS depressants, the risk of multiple intoxication increases, and the potential for fatal outcome must be considered.

Treatment of intoxication

Treatment is primarily symptomatic. Close monitoring of vital functions and fluid balance is essential. Airway patency must be ensured. Artificial ventilation should be performed if necessary. Hypotension may be treated with plasma expanders and, if needed, peripherally acting cardiovascular agents such as noradrenaline. To reverse benzodiazepine-induced CNS depression, the benzodiazepine antagonist flumazenil may be used. Hemodialysis is of limited value in benzodiazepine intoxication, but may be appropriate in cases of mixed poisoning.

Adverse reactions.

Benzodiazepine derivatives may cause dose-dependent depression of CNS function.

It is important to remember about limited-duration amnesia (anterograde amnesia) or memory impairment.

Abrupt discontinuation of the drug after its use in high doses or following prolonged administration of therapeutic doses may lead to withdrawal symptoms. Withdrawal symptoms may range from mild dysphoria and sleep disturbances to severe conditions including generalized seizures, tremor, abdominal and muscular cramps, vomiting, and increased sweating. To avoid withdrawal symptoms, the drug should be tapered gradually whenever possible.

As with other medicinal products of this pharmacological group, prolonged use increases the risk of dependence development.

There is evidence of tolerance development to the sedative effect of benzodiazepine derivatives.

Local symptoms: local phlebitis, pain immediately after injection, and redness around the injection site.

Rarely, hypersensitivity to benzyl alcohol may occur.

Reporting of suspected adverse reactions

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

Shelf life. 15 months.

Storage conditions.

Store and transport in a refrigerator at a temperature of +2 °C to +8 °C.

Store in the original packaging to protect from light.

Keep out of reach of children.

Packaging.

1 ml in an ampoule; 5 ampoules per blister; 1 or 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Kharkiv Pharmaceutical Enterprise "Zdorov'ya Narodu".

Manufacturer's address and location of business activity.

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