Alprazolam-zn

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

Composition:

Active ingredient: alprazolam;

1 tablet contains 0.25 mg or 0.5 mg of alprazolam;

Excipients: lactose monohydrate; microcrystalline cellulose; maize starch; magnesium stearate; colloidal anhydrous silicon dioxide; sodium docusate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: almost white, round cylindrical tablets with a flat surface, beveled edges, and a division line on one side.

Pharmacotherapeutic group. Anxiolytics. Benzodiazepine derivatives. ATC code N05BA12.

Pharmacological properties.

Pharmacodynamics.

The drug has anxiolytic, hypnotic-sedative, centrally acting muscle relaxant, and anticonvulsant properties.

The pharmacological effect of the drug is associated with enhancement of neuronal inhibition mediated by γ-aminobutyric acid (GABA) receptors.

Pharmacokinetics.

The drug is readily absorbed from the gastrointestinal tract. After oral administration, maximum plasma concentration is reached within 1–2 hours.

The average half-life is 12–15 hours. Repeated dosing may lead to accumulation; this should be taken into account in elderly patients and in patients with impaired renal or hepatic function. Alprazolam is 80% bound to human serum proteins. Alprazolam and its metabolites are excreted from the body predominantly in the urine.

Clinical characteristics.

Indications.

Short-term treatment of moderate to severe anxiety disorders and anxiety associated with depression. The medicinal product is indicated only when the disorder is severe, disabling, or causing the individual significant distress.

The medicinal product should not be used for the treatment of transient mild anxieties, such as anxiety or tension associated with everyday stress. Since the efficacy of alprazolam in depression and phobic or obsessive conditions has not been established, specific treatment may be required.

Contraindications.

Hypersensitivity to alprazolam and other benzodiazepines or to any of the excipients of the medicinal product, myasthenia (myasthenia gravis), severe hepatic insufficiency, sleep apnea syndrome, severe respiratory insufficiency.

Interaction with other medicinal products and other forms of interaction.

Opioids. Concomitant use of sedative medicines such as benzodiazepines or related medicines, e.g. alprazolam, with opioids increases the risk of sedation, respiratory depression, coma and death due to additive central nervous system (CNS) depressant effects. Dose and duration of concomitant use should be limited (see section "Special precautions for use"). Concomitant use with alcohol is not recommended. Alprazolam should be used with caution in combination with CNS depressants.

Enhanced central depressant effects may occur when used concomitantly with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressants, opioid analgesics, antiepileptic medicines, anaesthetics, and antihistamine medicinal products. When used with opioid analgesics, increased euphoria may also occur, potentially leading to increased psychological dependence. Pharmacokinetic interactions may occur during concomitant use of alprazolam with medicinal products that interfere with its metabolism.

CYP3A inhibitors. Compounds that inhibit certain liver enzymes (particularly CYP3A4) may increase alprazolam concentrations and enhance its activity. In vitro and clinical studies on alprazolam provide evidence of varying degrees of interaction and potential interaction with several medicinal products. Based on the extent of interaction and the type of available data, the following recommendations apply:

• concomitant use of alprazolam with ketoconazole, itraconazole, or other azole antifungal agents is not recommended;
• concomitant use of nefazodone or fluvoxamine increases the AUC of alprazolam by approximately 2-fold. Dose reduction is recommended, and special attention should be paid when alprazolam is used concomitantly with nefazodone, fluvoxamine, and cimetidine;
• caution is recommended when alprazolam is used concomitantly with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolides such as erythromycin, clarithromycin, and troleandomycin.

CYP3A4 inducers. Since alprazolam is metabolized by CYP3A4, inducers of this enzyme may increase the metabolism of alprazolam. The interaction between human immunodeficiency virus (HIV) protease inhibitors (e.g. ritonavir) and alprazolam is complex and time-dependent. Short-term, low-dose ritonavir leads to a significant reduction in alprazolam clearance, prolonged elimination half-life, and enhanced clinical effects. However, during long-term ritonavir therapy, enzyme induction of CYP3A compensates for this inhibition. Therefore, dosage adjustment or discontinuation of alprazolam may be necessary.

Digoxin. Increased plasma concentrations of digoxin have been observed during concomitant use, particularly in elderly individuals (aged 65 years and older). Therefore, patients receiving alprazolam and digoxin should be monitored for signs and symptoms associated with digoxin toxicity.

Special precautions for use.

Renal and hepatic impairment. Alprazolam should be used with caution in patients with impaired renal function or mild to moderate hepatic insufficiency.

Depression/anxiety. Benzodiazepines and benzodiazepine-like agents should not be used solely for the treatment of depression in patients with severe depression or anxiety associated with depression, as they may provoke or increase the risk of suicide. Therefore, alprazolam should be used cautiously and only for a limited duration in patients exhibiting signs and symptoms of depressive disorders or suicidal ideation.

Children. The safety and efficacy of alprazolam have not been established in children under 18 years of age; therefore, alprazolam is not recommended for use in this patient population.

Elderly patients. Benzodiazepines should be used with caution in elderly patients, as there is a risk of sedation and/or muscular weakness that may lead to sudden falls, often with serious consequences in this population group.

It is recommended to follow the general principle of using the lowest effective dose in elderly or debilitated patients to prevent the development of ataxia or excessive sedative effects (see section "Dosage and administration"). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Benzodiazepines should be used with particular caution in patients who abuse alcohol or drugs (see section "Interaction with other medicinal products and other forms of interaction").

Risk of concomitant use with opioids. Concomitant use of alprazolam and opioids may result in sedation, respiratory depression, coma, and fatal outcomes. Due to these risks, concomitant administration of sedative agents such as benzodiazepines or related agents, including alprazolam, with opioids should only occur in patients for whom alternative treatment options are not feasible.

If a decision is made to prescribe alprazolam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

Patients should be closely monitored for signs and symptoms of respiratory depression and sedation. Therefore, it is strongly recommended to inform patients and their caregivers about these symptoms (see section "Interaction with other medicinal products and other forms of interaction").

Dependence. The use of benzodiazepines may lead to the development of physical and psychological dependence. The risk of dependence increases with higher doses and longer duration of treatment; the risk is also higher in patients who abuse alcohol or drugs. The risk of dependence may also occur with therapeutic doses and/or in patients with individual risk factors. The risk of dependence is increased during combined use of multiple benzodiazepine-like agents, regardless of anxiolytic or hypnotic indication. Cases of abuse have also been reported.

Withdrawal symptoms: After physical dependence has developed, abrupt discontinuation of treatment will be accompanied by withdrawal symptoms. Manifestations may include headache, muscle pain, anxiety, tension, restlessness, confusion, irritability, and insomnia. In severe cases, symptoms may include derealization, depersonalization, numbness and tingling in the extremities, increased sensitivity to light, noise, and physical contact, hallucinations, or epileptic seizures.

When discontinuing alprazolam treatment, the dosage should be gradually reduced. It is expected that the daily dose of alprazolam will be decreased by no more than 0.5 mg every 3 days. For some patients, an even slower dose reduction may be necessary.

Insomnia and restlessness may occur during discontinuation of alprazolam treatment. This may be accompanied by other reactions, including mood changes, anxiety, sleep disturbances, and restlessness. Since the risk of withdrawal/abstinence phenomena is higher after abrupt discontinuation of treatment, it is recommended to gradually reduce the dosage by no more than 0.5 mg every 3 days. Some patients may require an even slower dose reduction.

Duration of treatment. The duration of treatment should be as short as possible (see section "Dosage and administration"), depending on the indication, but not exceeding 8–12 weeks, including tapering off the drug. The treatment period should not be extended without re-evaluation. The patient should be informed about the limited duration of treatment and the possibility of withdrawal syndrome.

It may be helpful to inform the patient at the beginning of treatment that it will be time-limited and to explain how the dose will be gradually reduced. Furthermore, it is important that the patient understands the possibility of rebound phenomena, thereby minimizing concern about such symptoms if they occur upon discontinuation of the medicinal product.

When short-acting benzodiazepines are used, abstinence phenomena may occur between therapeutic doses, especially at high therapeutic doses. When using long-acting benzodiazepines, switching to short-acting benzodiazepines should be avoided, as withdrawal symptoms may develop.

Amnesia. Benzodiazepines may cause anterograde amnesia. This most commonly occurs several hours after taking the drug, and to reduce this risk, patients should have uninterrupted sleep for 7–8 hours (see section "Undesirable effects").

Psychiatric and paradoxical reactions. If restlessness, excitement, irritability, aggressiveness, delirium, nightmares, hallucinations, psychosis, inappropriate behavior, or other adverse behavioral effects occur during benzodiazepine use, the drug should be discontinued. These manifestations occur most frequently in children and elderly patients.

Tolerance. Ineffectiveness of benzodiazepines may develop after repeated use over several weeks.

Episodes of hypomania and mania have been reported in association with alprazolam use in patients with depression.

Benzodiazepines are not recommended for primary treatment of psychoses.

If a patient has intolerance to certain sugars, they should consult a physician before using this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the teratogenicity of benzodiazepines and their impact on postnatal development and child behavior are conflicting. Data based on study results indicate that alprazolam use during the first trimester of pregnancy does not increase the risk of major congenital malformations in the child. However, some early case-control epidemiological studies have shown a twofold increase in the risk of oral clefts.

High-dose benzodiazepine treatment during the second and/or third trimester of pregnancy has been associated with reduced fetal movements and fetal heart rate abnormalities. Use of the drug during the third trimester of pregnancy, even at low doses, may result in a floppy infant syndrome characterized by axial hypotonia and sucking difficulties, leading to reduced infant body weight. These signs are reversible but may last from 1 to 3 weeks, depending on the drug's half-life. High-dose use may lead to respiratory depression or apnea and hypothermia in newborns. Additionally, withdrawal symptoms in newborns, such as hyperexcitability, agitation, and tremor, may occur several days after birth, even in the absence of floppy infant syndrome. The onset of withdrawal symptoms after birth depends on the half-life of the substance.

The medicinal product should not be used during pregnancy unless the woman's clinical condition requires treatment. If alprazolam is used during pregnancy or if a patient becomes pregnant while taking alprazolam, she should be informed of the potential risk to the fetus.

If alprazolam treatment is necessary during the third trimester of pregnancy, high doses should be avoided, and withdrawal syndrome and/or floppy infant syndrome in newborns should be monitored.

Breastfeeding. Alprazolam passes into breast milk in small amounts. Nevertheless, the use of the medicinal product is not recommended during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

The medicinal product may affect psychomotor performance (sedation, amnesia, impaired attention concentration, and muscle function), especially when used concomitantly with alcohol or other central nervous system depressants. Therefore, patients should refrain from driving or operating machinery until it is established that the drug does not cause drowsiness or dizziness.

Method of Administration and Dosage.

Dosage.

Anxiety. From 0.25 mg to 0.5 mg three times daily, increasing if necessary to a total daily dose of 3 mg.

Elderly patients or presence of debilitating diseases. 0.25 mg two to three times daily, gradually increasing if necessary and well tolerated.

If adverse effects occur, the dose should be reduced. It is advisable to regularly review treatment and discontinue it as soon as possible. If long-term treatment is required, periodic treatment may be considered to minimize the risk of dependence.

Method of Administration. For oral use.

Treatment should be as short as possible. It is recommended to re-evaluate the patient after no more than 4 weeks of treatment to determine the need for continued therapy, especially if the patient is asymptomatic. The total duration of treatment should not exceed 8–12 weeks, including the tapering-off process.

In some cases, extension of the maximum treatment period may be necessary; if so, this should not occur without re-evaluation of the patient’s condition by specialist assessment. As with all benzodiazepines, physicians should be aware that prolonged use may lead to dependence in some patients.

Optimal dosage should be based on symptom severity and individual patient response. The lowest effective dose that controls symptoms should be used. Dosage should be reviewed at intervals of no more than 4 weeks. The usual dosage is indicated below; in some patients requiring higher doses, the dose should be increased cautiously to avoid adverse effects. If a higher dose is needed, the evening dose should be increased before the daytime doses. In general, patients who have not previously received psychotropic medications will require lower doses than those who have received such treatment, or patients with a history of chronic alcoholism.

Treatment should always be discontinued gradually. When discontinuing alprazolam, the dose should be tapered slowly according to sound medical practice. It is recommended to reduce the daily dose of alprazolam by no more than 0.5 mg every 3 days. Some patients may require an even slower dose reduction (see section "Special Precautions for Use").

Elderly patients. Reduced drug clearance and, as with other benzodiazepines, increased sensitivity to the drug are observed in elderly patients (see section "Pharmacokinetics").

Children.

The safety and efficacy of alprazolam in children and adolescents under 18 years of age have not been established. There are no data.

Overdose.

Overdose rarely leads to life-threatening consequences, except when combined with other CNS depressants (including alcohol). In such cases, it should be considered that the patient may have taken multiple medications.

Symptoms: overdose of benzodiazepines typically manifests as varying degrees of CNS depression, ranging from drowsiness to coma. In mild cases, symptoms include: drowsiness, confusion, and lethargy; in more severe cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma, and very rarely, fatal outcome.

Treatment: following oral benzodiazepine overdose, emesis should be induced (within 1 hour) and activated charcoal administered if the patient is conscious, or gastric lavage performed if the patient is unconscious. Particular attention in resuscitation should be paid to respiratory and cardiovascular function.

Flumazenil may be used as an antidote.

Adverse reactions.

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

The following adverse effects have been reported during treatment with alprazolam, with the following frequencies: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1000, < 1/100); rare (> 1/10000, < 1/1000); very rare (< 1/10000); not known (frequency cannot be estimated from available data).

* - post-marketing observations

Withdrawal symptoms may occur after abrupt dosage reduction or abrupt discontinuation of benzodiazepines, including alprazolam. These symptoms may range from mild dysphoria and insomnia to a full-blown withdrawal syndrome, which may include abdominal cramps, muscle spasms, vomiting, sweating, tremor, and convulsions. In addition, withdrawal seizures may occur during rapid dose reduction or abrupt discontinuation of the drug.

Amnesia. Anterograde amnesia may occur with therapeutic doses, but the risk increases with higher doses. Amnestic effects may be associated with inappropriate behavior.

Depression. Pre-existing depression may become apparent during benzodiazepine therapy.

Psychiatric and paradoxical reactions. Reactions such as restlessness, stimulation, irritability, aggression, delirium, nightmares, hallucinations, psychoses, inappropriate behavior, and other adverse behavioral effects have been reported with benzodiazepines or benzodiazepine-like agents. These adverse effects may be quite serious. They occur more frequently in children and elderly patients.

In many spontaneous reports of adverse behavioral effects, patients were receiving other centrally acting agents concomitantly and/or were characterized as having psychiatric disorders. Patients with a history of personality disorders involving violent or aggressive behavior, or with alcohol or psychotropic substance abuse, may be more prone to such reactions. Cases of irritability, hostility, and obsessive thoughts have been reported during discontinuation of the drug in patients with post-traumatic stress disorder.

Dependence. Use (even at therapeutic doses) may lead to the development of physical dependence; discontinuation of therapy may result in withdrawal syndrome (see section "Special precautions"). Psychological dependence is also possible. Cases of benzodiazepine abuse have been reported.

Reporting of adverse reactions

Reporting of adverse reactions following marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at: 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. 10 tablets per blister; 1 or 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Limited liability company "Kharkiv Pharmaceutical Enterprise "Zdorovya Narodu".

Manufacturer's address and location of operations. 41 Kulikivska Street, Kharkiv, Kharkiv Oblast, 61002, Ukraine.