Alprazolam grindex

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ALPRAZOLAM GRINDEKS (ALPRAZOLAM GRINDEKS)

Composition:

Active substance: alprazolam;

One tablet contains 0.25 mg or 0.5 mg or 1 mg of alprazolam;

Excipients: lactose monohydrate; microcrystalline cellulose type 101 (E 460); pregelatinized corn starch; mixture of sodium lauryl sulfate and sodium benzoate (85/15) containing: sodium lauryl sulfate and sodium benzoate (E 211); magnesium stearate (E 572); colloidal anhydrous silicon dioxide (E 551); iron oxide red (E 172) (only for 0.5 mg tablets); indigocarmine (E 132) (only for 1 mg tablets); ethanol (96%); purified water.

Pharmaceutical form. Tablets.

Main physicochemical properties:

0.25 mg tablets

White or almost white, oval-shaped tablets with a score line on one side and engraved "0.25" on the other. Tablet dimensions: length 10 mm and width 5 mm. The tablet can be divided into two equal halves.

0.5 mg tablets

Light pink to pink, oval-shaped tablets with a score line on one side and engraved "0.5" on the other. Tablet dimensions: length 10 mm and width 5 mm. The tablet can be divided into two equal halves.

1 mg tablets

Light blue to blue, oval-shaped tablets with a score line on one side and engraved "1" on the other. Tablet dimensions: length 10 mm and width 5 mm. The tablet can be divided into two equal halves.

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

Pharmacological Properties

Pharmacodynamics

Alprazolam is a psychotropic substance belonging to the class of 1,4-triazolobenzodiazepines, which binds with high affinity to specific benzodiazepine receptors in the central nervous system (CNS). Alprazolam enhances the inhibitory effect of GABA-ergic neurotransmission on various neuronal centers. As a result, there is suppression of tension, agitation, and anxiety, as well as sedative and hypnotic effects. In addition, alprazolam exhibits muscle relaxant and anticonvulsant properties.

Pharmacokinetics

After oral administration, peak plasma concentrations are reached approximately 1.7 hours post-dose. Following a single oral dose of 0.5 mg, the mean maximum concentration was 7.1 ng/mL. There is a linear relationship between dose and plasma concentration. At least 80% of the oral dose is absorbed. Approximately 70% of the absorbed dose is bound to plasma proteins.

Alprazolam is extensively metabolized in the liver, primarily to hydroxylated metabolites, although about 20% of the dose is excreted unchanged.

Elimination occurs primarily via the kidneys; 80% of the dose is excreted in urine and only 7% in feces. The mean elimination half-life is 10–12 hours.

Clinical Characteristics

Indications

Short-term symptomatic treatment of anxiety in adult patients. The medicinal product is indicated only when the disorder is severe, disabling, or subjecting the individual to significant distress.

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 sedatives such as benzodiazepines or related medicinal products like alprazolam 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 for use"). Concomitant use with alcohol is not recommended. Alprazolam should be used with caution when combined with CNS depressants.

Enhanced central depressant effects may occur when alprazolam is used concomitantly with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressants, opioid analgesics, antiepileptic drugs, anesthetics, and sedative antihistamines. When opioid analgesics are taken, increased euphoria may also be observed, potentially leading to increased psychological dependence.

Inhibitors of CYP3A4

Compounds that inhibit certain liver enzymes (particularly cytochrome P450 3A4) may increase alprazolam concentrations and enhance its activity. Data from clinical studies with alprazolam, in vitro studies with alprazolam, and clinical studies with drugs metabolized similarly to alprazolam indicate varying degrees of interaction and potential interaction with alprazolam for several medicinal products. Based on the extent of interaction and 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 co-administering alprazolam with fluoxetine, propoxyphene, oral contraceptives, sertraline, diltiazem, or macrolides such as erythromycin, clarithromycin, and troleandomycin.

Inducers of CYP3A4

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 use of low doses of ritonavir leads to a marked reduction in alprazolam clearance, prolonged elimination half-life, and enhanced clinical effects. However, with prolonged ritonavir therapy, enzyme induction of CYP3A compensates for this inhibition. Therefore, dosage adjustment or discontinuation of alprazolam may be necessary.

Theophylline

Patients receiving alprazolam and theophylline concomitantly have significantly lower plasma concentrations of alprazolam compared to those receiving alprazolam alone, likely due to induced metabolism. The clinical significance of this interaction has not been established.

Carbamazepine appears to induce alprazolam metabolism, resulting in reduced efficacy. The clinical significance of this interaction has not been established. Similar effects may be expected when alprazolam is used concomitantly with rifampicin or St. John’s wort.

Effect of alprazolam on the pharmacokinetics of other medicinal products

Digoxin

Increased plasma levels of digoxin have been reported when used concomitantly with alprazolam, particularly in elderly individuals (>65 years). Therefore, patients receiving alprazolam and digoxin concomitantly should be closely monitored for signs and symptoms of digoxin toxicity.

Muscle relaxants

Patients should be aware of an enhanced muscle relaxant effect (risk of falls) when alprazolam is used during therapy with muscle relaxants, especially at the beginning of treatment.

Plasma concentrations of imipramine and its metabolite desipramine may increase by 30% when used concomitantly with alprazolam due to inhibition of metabolism.

Effect of other medicinal products on the pharmacokinetics of alprazolam

Combinations to be avoided

Dextropropoxyphene may inhibit the metabolism/reduce the clearance of alprazolam, leading to increased plasma concentrations of alprazolam and thus enhanced effects. Concomitant treatment with dextropropoxyphene should be avoided.

Nefazodone inhibits CYP3A4-mediated oxidation of alprazolam, resulting in a doubling of alprazolam plasma concentrations and an increased risk of CNS effects. Therefore, when used in combination, the dose of alprazolam should be reduced by half.

Interactions to be considered, which may require dose adjustment

Oral contraceptives: oral contraceptives may inhibit the metabolism of benzodiazepines, particularly the oxidation of alprazolam, potentially leading to increased plasma concentrations and enhanced effects of alprazolam.

Omeprazole: may inhibit the metabolism of alprazolam, leading to increased plasma concentrations and enhanced effects of alprazolam.

Special precautions for use

Duration of treatment

The duration of treatment should be as short as possible and should not exceed 2–4 weeks (see section "Posology and method of administration"). The treatment period should not be extended without re-evaluation of the patient's condition.

At the beginning of treatment, it may be helpful to inform the patient that treatment will be time-limited and to explain how the dose will be gradually reduced. When using benzodiazepines with a short duration of action, withdrawal phenomena may occur within the therapeutic dose range, especially at high therapeutic doses. When using long-acting benzodiazepines, switching to short-acting benzodiazepines should be avoided, as withdrawal symptoms may develop.

Renal and hepatic impairment

Use with caution in patients with impaired renal function or mild to moderate hepatic insufficiency.

Depression / suicidal thoughts

Benzodiazepines and benzodiazepine-like drugs should not be used alone for the treatment of depression, as they may provoke or increase the risk of suicide. Therefore, alprazolam should be used cautiously and only for a limited period in patients showing signs and symptoms of depressive disorder or with suicidal ideation.

Prescribing the medicinal product to patients with severe depression or suicidal thoughts should be done with appropriate precautionary measures, including controlling the required number of tablets for appropriate treatment.

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, which 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 "Posology and method of administration").

Respiratory insufficiency

A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Alcohol

Benzodiazepines should be used with special 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 death. Due to these risks, concomitant prescription of sedative medicinal products such as benzodiazepines or related substances, including alprazolam, with opioids should only occur in patients for whom alternative treatment options are not possible.

If a decision is made to prescribe alprazolam together 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, patients and their caregivers should be informed 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 developing dependence may also occur with the use of the drug at 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.

Fatal outcomes due to overdose have been reported in cases of alprazolam abuse in combination with other central nervous system (CNS) depressants, including opioids, other benzodiazepines, and alcohol. These risks should be considered when prescribing or dispensing alprazolam. To reduce these risks, the smallest necessary amount of the drug should be prescribed, and patients should be advised on proper storage and disposal of unused medication.

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, hyperacusis, 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.

Rebound insomnia and anxiety

Rebound insomnia and anxiety may occur during withdrawal from alprazolam treatment. This may be accompanied by other reactions, including mood changes, mild dysphoria, anxiety, sleep disturbances, abdominal and muscle cramps, vomiting, sweating, tremor, and restlessness. Since the risk of withdrawal/abstinence phenomena is higher after abrupt discontinuation of treatment, gradual dose reduction is recommended to avoid withdrawal symptoms.

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, aggression, 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

Loss of effectiveness of benzodiazepines may develop after repeated use over several weeks.

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

Benzodiazepines are not recommended for primary treatment of psychoses.

Excipients

Lactose

This medicinal product is contraindicated in patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Sodium

One tablet of this medicinal product contains less than 1 mmol of sodium (23 mg), i.e., it is considered practically sodium-free.

Sodium benzoate

This medicinal product contains 0.12 mg of sodium per tablet.

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 the use of alprazolam during the first trimester of pregnancy does not increase the risk of major congenital malformations. However, some early case-control epidemiological studies have shown a twofold increase in the risk of oral clefts.

Treatment with benzodiazepines at high doses during the second and/or third trimester of pregnancy has been associated with reduced fetal movements and fetal heart rate abnormalities. If the drug is used during the third trimester of pregnancy, even at low doses, floppy infant syndrome may occur, 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 elimination half-life. High-dose use may result in respiratory depression or apnea and hypothermia in newborns. Additionally, withdrawal symptoms in newborns, such as hyperexcitability, agitation, and tremor, may appear several days after birth, even in the absence of floppy infant syndrome. The onset of withdrawal symptoms after birth depends on the elimination half-life of the substance.

This medicinal product should not be used during pregnancy unless the clinical condition of the woman 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 treatment with alprazolam is necessary during the third trimester of pregnancy, high doses should be avoided, and withdrawal syndrome and/or floppy infant syndrome should be monitored in newborns.

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 vehicles or operating machinery

Sedation, amnesia, impaired attention, and muscle function disturbances may negatively affect the ability to drive vehicles or operate machinery. The probability of impaired alertness may be increased if sleep duration is insufficient. These effects are enhanced by alcohol (see section "Interaction with other medicinal products and other forms of interaction"). Patients should be warned against driving vehicles or operating machinery while taking this drug.

Method of Administration and Dosage

The dose and duration of treatment should be adjusted according to individual response, indications, and severity of the disease.

Treatment Duration

Alprazolam Grynideks should be used at the lowest effective dose for the shortest possible time, and for a maximum of 2–4 weeks, including the period of gradual dose reduction. The need for continued treatment should be frequently reassessed. Prolonged treatment is not recommended. The risk of dependence may increase with higher doses and longer duration of treatment (see section "Special Precautions").

Treatment is usually initiated at a dose of 0.5 mg to 1 mg daily in divided doses, increasing (by no more than 1 mg every 3–4 days) to the level of optimal control, typically 3–4 mg daily.

The dose should be gradually reduced to avoid withdrawal symptoms.

Elderly Patients

For elderly or debilitated patients, the initial dose should be 0.25 mg twice daily, with gradual dose escalation as needed and provided tolerance is maintained.

Method of Administration

Alprazolam Grynideks is intended for oral administration.

Treatment should begin with the lowest recommended dose. The maximum dose should not be exceeded.

Initial doses may be taken at bedtime to minimize daytime drowsiness. If adverse effects occur with the initial dose, the dose should be reduced.

Children

The safety and efficacy of alprazolam in children and adolescents under 18 years of age have not been established.

Therefore, alprazolam is not recommended for use in children and adolescents under 18 years of age.

Overdose

Symptoms

Alprazolam overdose is not usually life-threatening unless combined with other CNS depressants such as opioids, other benzodiazepines, or alcohol.

In such cases, it should be considered that the patient may have taken multiple drugs (combined intoxication with psychoactive substances). Benzodiazepine overdose 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.

Toxicity

Blood levels of alprazolam reported in fatal poisonings vary widely. Toxic plasma concentrations of alprazolam range from 0.1–0.4 µg/mL, whereas postmortem blood concentrations have been reported in the range of 2.1–2.3 µg/mL in some cases.

Treatment

The primary method of treating acute alprazolam overdose is supportive therapy, which may include ensuring adequate airway patency and monitoring respiratory and cardiovascular functions. Intravenous (i.v.) access should be established for fluid administration.

Patients with mild signs of intoxication who remain conscious should be allowed to sleep under medical supervision. If the patient is alert, activated charcoal may be administered within one hour of drug ingestion to reduce absorption, but the benefit/risk ratio must be considered (due to the risk of aspiration).

Forced diuresis or hemodialysis are not effective.

In severe cases, flumazenil (a specific benzodiazepine antagonist) may be used as an adjunct to respiratory support treatment in overdose. Flumazenil may increase the risk of seizures.

Adverse Reactions

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

The following categories are used to express the frequency of adverse reactions:

The following adverse effects have been observed 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), frequency not known (frequency cannot be estimated from available data).

Very common (≥1/10)	Common (from ≥ 1/100 to < 1/10)	Uncommon (from ≥ 1/1000 to < 1/100)	Rare (≥1/10000 to <1/1000)	Very rare (<1/ 10,000)	Frequency not known (cannot be estimated from available data)
Endocrine system disorders
					Hyperprolactinaemia*
Metabolism and nutrition disorders
	Decreased appetite
Psychiatric disorders
Depression	Confusional state, disorientation, decreased libido, anxiety, insomnia, nervousness, increased libido*	Mania* (see section Special precautions for use), hallucinations*, anger*, agitation*, drug dependence			Hypomania*, aggression*, hostility*, thought disorder*, psychomotor hyperactivity*, medication abuse
Nervous system disorders
Sedation, somnolence, ataxia, memory impairment, dysarthria, dizziness, headache	Balance disorder, coordination disturbance, attention disturbance, hypersomnia, lethargy, tremor	Amnesia			Autonomic nervous system imbalance*, dystonia*
Eye disorders
	Blurred vision
Gastrointestinal disorders
Constipation, dry mouth	Nausea	Vomiting			Gastrointestinal disorders*
Hepatobiliary disorders
					Hepatitis*, liver function abnormalities*, jaundice*
Skin and subcutaneous tissue disorders
	Dermatitis*				Angioneurotic edema*, photosensitivity*
Musculoskeletal and connective tissue disorders
		Muscle weakness
Renal and urinary disorders
		Urinary incontinence*			Urinary retention*
Reproductive system and breast disorders
	Sexual dysfunction*	Irregular menstruation*
General disorders
Increased fatigue, irritability		Withdrawal syndrome*			Peripheral edema*
Investigations
	Increased or decreased body weight				Increased intraocular pressure*

* Adverse reactions identified during the post-marketing period

Withdrawal symptoms

Withdrawal symptoms may occur after abrupt dosage reduction or abrupt discontinuation of benzodiazepines, including alprazolam. They may range from mild dysphoria and insomnia to a full-blown withdrawal syndrome, which may include abdominal and muscle cramps, 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 be unmasked during benzodiazepine therapy (see section "Special precautions").

Psychiatric and paradoxical reactions

Reactions such as restlessness, excitement, irritability, aggression, delusions, nightmares, hallucinations, psychoses, inappropriate behavior, and other adverse behavioral effects have been reported during use of benzodiazepines or benzodiazepine-like agents. These adverse effects may be severe. They occur more frequently in children and elderly patients.

Dependence. Use (even at therapeutic doses) may lead to the development of physical dependence; discontinuation of therapy may lead to 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 important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

0.25 mg – 18 months.

0.5 mg – 2 years.

1 mg – 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets in a blister; 1, 2, 3, 5, 6 or 0 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer

JSC "Grindeks".

Manufacturer's address and place of business

53 Krustpils Street, Riga, LV-1057, Latvia.

Tel./fax: +371 67083205 / +371 67083505

E-mail: [email protected]

Marketing Authorization Holder

JSC "Grindeks".

Address of the Marketing Authorization Holder

53 Krustpils Street, Riga, LV-1057, Latvia.

Tel./fax: +371 67083205 / +371 67083505

E-mail: [email protected]