Neurol^® (Tablets) Instructions for Use

ATC Code

N05BA12 (Alprazolam)

Active Substance

Alprazolam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anxiolytic (tranquilizer)

Pharmacotherapeutic Group

Anxiolytic agent (tranquilizer)

Pharmacological Action

Alprazolam exerts anxiolytic, central muscle relaxant, anticonvulsant, sedative-hypnotic, and antipanic effects. It has a depressant effect on the CNS, primarily realized in the thalamus, hypothalamus, and limbic system. It enhances the inhibitory action of gamma-aminobutyric acid (GABA), which is one of the main mediators of pre- and postsynaptic inhibition of nerve impulse transmission in the CNS. It also possesses anxiolytic, sedative, muscle relaxant, and anticonvulsant properties.

The mechanism of action of alprazolam is determined by the stimulation of benzodiazepine receptors of the supramolecular GABA-benzodiazepine-chloride ionophore receptor complex, leading to the activation of the GABA receptor, which causes a decrease in the excitability of subcortical brain structures and inhibition of polysynaptic spinal reflexes.

The anxiolytic effect is manifested in a reduction of emotional tension and a weakening of symptoms of anxiety and fear.

Pronounced anxiolytic activity is combined with a moderate hypnotic effect; it shortens the sleep onset period, increases sleep duration, and reduces the number of nighttime awakenings. The mechanism of the hypnotic action involves the inhibition of cells in the reticular formation of the brainstem. It reduces the impact of emotional, vegetative, and motor stimuli that disrupt the sleep onset mechanism. It has virtually no effect on the cardiovascular and respiratory systems.

Pharmacokinetics

After oral administration, C_max in plasma is reached in approximately 1-2 hours. After a single oral dose of 0.5 mg, the mean maximum concentration was 7.1 ng/mL. There is a linear relationship between the dose of alprazolam and plasma concentration. Approximately 80% of the dose is absorbed after oral administration.

About 80% of the drug is bound to plasma proteins. It can cross the placenta, the blood-brain barrier (BBB), and penetrate into breast milk. Steady-state plasma concentration is usually reached within several (2-3) days.

Alprazolam is actively metabolized in the liver, the main metabolite being the alpha-hydroxy metabolite, which possesses biological activity.

Elimination of the drug from the body occurs mainly through the kidneys as compounds with glucuronic acid. T_1/2 is approximately 11-16 hours. Accumulation upon repeated administration is minimal (belongs to benzodiazepines with short or intermediate T_1/2), elimination after discontinuation of treatment is rapid.

Indications

• Anxiety disorders associated with depression;
• Neurotic depressions with anxious symptomatology of various origins;
• Panic disorders.

ICD codes

Dosage Regimen

Tablets

Orally, 2-3 times/day, regardless of meals. The dose of the drug is selected individually and adjusted during treatment depending on the effect and individual tolerance. The use of the minimum effective doses is recommended.

For anxiety disorders, the initial dose is 0.25 mg-0.5 mg 3 times/day. If necessary, this dose can be increased to 4 mg/day (divided into several doses).

In elderly patients, the initial dose is 0.25 mg 2-3 times/day.

For anxiety disorders associated with depression, the initial dose is 0.5 mg 3 times/day. If necessary, the dose is increased to 4.5 mg/day. The initial dose may be prescribed at bedtime to minimize daytime drowsiness. The duration of treatment is 4-12 weeks. Discontinuation of the drug should be done with great caution. The dose should be reduced gradually and slowly, by no more than 0.5 mg-1 mg at bedtime or 0.5 mg 3 times/day. For most patients, a dose of 4-6 mg/day for 4-12 weeks is sufficient. In individual cases, if necessary, the dose can be increased to 10 mg/day (but by no more than 1 mg every 3-4 days), and the duration of treatment can be extended to eight months.

When treating elderly and debilitated patients, lower doses should be used: initial – 0.25 mg 2-3 times/day, if necessary and well tolerated, it is gradually increased to 0.5-0.75 mg/day.

Adverse Reactions

Side effects, as a rule, occur at the beginning of treatment and gradually disappear with further use of the drug or dose reduction.

From the CNS at the beginning of treatment (especially in elderly patients) – drowsiness, feeling of fatigue, dizziness, impaired concentration, ataxia, disorientation, slowing of mental and motor reactions; rarely – headache, euphoria, depressed mood, tremor, memory impairment, impaired coordination of movements, confusion, dystonic extrapyramidal reactions (uncontrolled movements, including eyes), muscle weakness, slurred speech; extremely rarely – paradoxical reactions (aggressive outbursts, confusion, psychomotor agitation, fear, suicidal tendency, muscle spasm, hallucinations, anxiety, insomnia).

From the hematopoietic system leukopenia, neutropenia, agranulocytosis (chills, hyperthermia, sore throat, unusual fatigue or weakness), anemia, thrombocytopenia.

From the digestive system dry mouth or salivation, heartburn, nausea, vomiting, anorexia, constipation, diarrhea; impaired liver function, increased activity of hepatic transaminases and alkaline phosphatase (ALP), jaundice.

From the genitourinary system urinary incontinence, urinary retention, impaired renal function, decreased or increased libido, dysmenorrhea.

Allergic reactions skin rash, itching.

Effect on the fetus teratogenicity (especially the first trimester), CNS depression, respiratory depression and suppression of the sucking reflex in newborns whose mothers used the drug.

Other habituation, drug dependence; decreased BP; rarely – visual impairment (diplopia), weight loss, tachycardia. With a sharp dose reduction or discontinuation – withdrawal syndrome (increased irritability, sleep disturbance, dysphoria, spasm of smooth muscles of internal organs and skeletal muscles, depersonalization, increased sweating, depressed mood, nausea, vomiting, tremor, perception disorders, including hyperacusis, paresthesia, photophobia; tachycardia, convulsions, rarely – acute psychosis).

Contraindications

• Coma;
• Shock;
• Closed-angle glaucoma;
• Myasthenia gravis;
• Acute poisoning with alcohol, narcotics, hypnotics, and psychotropic drugs;
• Severe chronic obstructive pulmonary disease;
• Severe depression (suicide attempts);
• Sleep apnea syndrome;
• Severe impairment of renal and hepatic function;
• Pregnancy (especially the first trimester) see ‘Special Precautions’, breastfeeding period;
• The safety of alprazolam use in children and adolescents (under 18 years) has not been established;
• Hypersensitivity to alprazolam or other benzodiazepines.

With caution cerebral and spinal ataxia, history of drug dependence, tendency to abuse psychotropic drugs, hyperkinesis, organic brain diseases, psychosis (paradoxical reactions are possible), hypoproteinemia, old age.

Use in Pregnancy and Lactation

During pregnancy, it should be used only in exceptional cases and only for vital indications. It has a toxic effect on the fetus and increases the risk of congenital malformations when used in the first trimester of pregnancy. The use of therapeutic doses in later stages of pregnancy can cause CNS depression in the newborn. Continuous use during pregnancy can lead to physical dependence with the development of withdrawal syndrome in the newborn.

Use immediately before or during childbirth can cause respiratory depression, decreased muscle tone, hypotension, hypothermia, and weak sucking reflex in the newborn (so-called “floppy infant syndrome”).

Use during lactation is contraindicated.

Use in Hepatic Impairment

Contraindications: severe impairment of hepatic function.

Use in Renal Impairment

Contraindications: severe impairment of renal function.

Pediatric Use

The safety of alprazolam use in children and adolescents (under 18 years) has not been established.

Geriatric Use

When treating elderly and debilitated patients, lower doses should be used: initial – 0.25 mg 2-3 times/day, if necessary and well tolerated, it is gradually increased to 0.5-0.75 mg/day.

Special Precautions

During treatment with alprazolam, patients are strictly prohibited from consuming alcohol (ethanol).

In renal/hepatic insufficiency and during long-term treatment, monitoring of peripheral blood counts and liver enzymes (transaminases) is necessary.

Patients who have not previously taken psychotropic drugs “respond” to the drug at lower doses compared to patients who have previously taken antidepressants, anxiolytics, or suffer from alcoholism.

In endogenous depressions, Alprazolam can be used in combination with antidepressants.

When using alprazolam in depressed patients, cases of hypomanic and manic state development have been noted.

Like other benzodiazepines, Alprazolam has the ability to cause drug dependence with long-term use in high doses (more than 4 mg/day).

If unusual reactions occur in patients, such as increased aggressiveness, acute states of agitation, feelings of fear, suicidal thoughts, hallucinations, increased muscle cramps, difficulty falling asleep, shallow sleep, treatment should be discontinued.

Children, especially at a young age, are very sensitive to the CNS depressant effect of benzodiazepines.

Overdose

Drug overdose (ingestion of 500-600 mg).

Symptoms: drowsiness, confusion, decreased reflexes, nystagmus, tremor, bradycardia, shortness of breath or difficulty breathing, decreased BP, coma.

Treatment: gastric lavage, administration of activated charcoal. Symptomatic therapy (maintenance of respiration and BP), administration of flumazenil (in a hospital setting). Hemodialysis is not very effective.

Drug Interactions

Alprazolam enhances the effect of other psychotropic drugs, anticonvulsants and antihistamines, ethanol, and drugs that have a depressant effect on the CNS.

Inhibitors of microsomal oxidation increase the risk of toxic effects.

Inducers of hepatic microsomal enzymes decrease effectiveness. Antihypertensive agents may enhance the severity of BP reduction.

Clozapine – possible enhancement of respiratory depression.

Reduces the effectiveness of levodopa in patients with parkinsonism.

Potentially possible increase in the toxicity of zidovudine.

Alprazolam at a dose of 4 mg/day increases plasma concentrations of imipramine and desipramine (by 31% and 20%, respectively) when taken concomitantly.

The metabolic clearance of alprazolam is decreased with the concomitant use of usual therapeutic doses of cimetidine and antibiotics from the macrolide group.

Caution should be exercised and consideration given to reducing the doses of alprazolam when taken with cimetidine, macrolides, nefazodone, fluvoxamine, fluoxetine, propoxyphene, sertraline, diltiazem, digoxin, and oral contraceptives.

Storage Conditions

Store at a temperature from 10°C (50°F) to 25°C (77°F) in a dry place, protected from light and out of the reach of children.

Shelf Life

Shelf life – 3 years.

Dispensing Status

By prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.