Aminazin-zdorov'ya: detailed information

INSTRUCTIONS FOR MEDICAL USE of the medicinal product AMINAZIN-ZDOROVYE (AMINAZIN-ZDOROVYE)

Composition:

Active substance: chlorpromazine;

One tablet contains chlorpromazine hydrochloride 50 mg or 100 mg;

Excipients: celactose (a mixture of monohydrate lactose and powdered cellulose (75:25)), colloidal anhydrous silicon dioxide, aluminum hydroxide, calcium stearate, stearic acid, talc, hypromellose, titanium dioxide (E 171), yellow FCF (E 110).

Medicinal form. Film-coated tablets.

Main physico-chemical properties: biconvex film-coated tablets of light orange to dark orange color. Two layers are visible in cross-section.

Pharmacotherapeutic group. Antipsychotic agents. Chlorpromazine. ATC code N05A A01.

Pharmacological properties.

Pharmacodynamics. An antipsychotic, neuroleptic, sedative, myorelaxant, and antiemetic agent. It exerts blocking effects on dopaminergic and adrenergic receptors. The main characteristic of the drug is the combination of antipsychotic action with the ability to influence the emotional sphere.

The mechanism of antipsychotic action is due to blockade of postsynaptic dopaminergic receptors in the mesolimbic structures of the brain. As a result, delusions and hallucinations are attenuated or completely eliminated, psychomotor agitation is suppressed, affective responses, anxiety, and apprehension are reduced, and motor activity decreases. Due to blockade of dopaminergic receptors, secretion of prolactin by the pituitary gland increases.

By blocking α-adrenergic receptors, it produces a pronounced sedative effect. The presence of strong sedative action is one of the main distinguishing features of chlorpromazine compared to other neuroleptics. The overall calming effect is combined with suppression of conditioned reflex activity, particularly motor-protective reflexes, reduced spontaneous motor activity, relaxation of skeletal muscles, and decreased responsiveness to endogenous and exogenous stimuli, while consciousness is preserved.

It exerts a pronounced central and peripheral antiemetic effect; the central effect is due to inhibition or blockade of dopaminergic D2 receptors in the chemoreceptor trigger zone of the medulla oblongata, while the peripheral effect results from blockade of the vagus nerve in the gastrointestinal tract. The antiemetic effect is enhanced by the anticholinergic, sedative, and antihistaminic properties of chlorpromazine.

The anticholinergic effect is due to competitive blockade of M-cholinergic receptors; the anxiolytic, sedative, and analgesic effects result from reduced excitation in the reticular formation of the brainstem.

It moderately reduces the intensity of inflammatory reactions, decreases vascular permeability, reduces the activity of kinins and hyaluronidase, and exhibits weak antihistaminic activity. It reduces systolic and diastolic blood pressure and causes tachycardia. It has pronounced cataleptogenic properties. It suppresses the release of hypothalamic and pituitary hormones (although it enhances prolactin secretion). It produces weak or moderate extrapyramidal effects. It exerts a hypothermic effect.

It potentiates the action of analgesics, local anesthetics, hypnotics, and anticonvulsants.

Pharmacokinetics. Poorly absorbed in the gastrointestinal tract. Maximum plasma concentration (Cmax) is reached within 2–4 hours. Plasma protein binding is 95–98%. It undergoes first-pass metabolism. Widely distributed throughout the body and crosses the blood-brain barrier, achieving higher concentrations in the brain than in plasma. Chlorpromazine and its metabolites cross the placental barrier and are excreted into breast milk. It is intensively metabolized in the liver, forming several active and inactive metabolites. It is excreted via the kidneys and through the intestine with bile as metabolites. The elimination half-life is approximately 30 hours; elimination of metabolites may be prolonged.

Marked variability in pharmacokinetic parameters has been observed in the same patient. There is no direct correlation between plasma concentrations of chlorpromazine and its metabolites and the therapeutic effect.

Clinical characteristics.

Indications. In psychiatry – chronic paranoid and/or hallucinatory states, including in patients with schizophrenia (hallucinatory-delusional, hebephrenic, catatonic syndromes); manic excitement in manic-depressive psychosis; agitated depression (in involutional and manic-depressive psychosis).

In neurology – increased muscle tone, torpid pain syndrome (in combination with analgesics).

Persistent hiccups (for treatment of adults).

Contraindications. Hypersensitivity to any component of the drug. Severe impairment of liver function (cirrhosis, hepatitis, hemolytic jaundice) and/or kidney function (nephritis, acute pyelitis, amyloidosis of the kidneys); disorders of the hematopoietic organs; progressive systemic diseases of the brain and spinal cord (slow neuroinfections, multiple sclerosis); myxedema; severe cardiovascular diseases (decompensated heart failure and heart defects, severe myocardiodystrophy and arterial hypotension, rheumatic heart disease in late stages); thromboembolism; late stage of bronchiectatic disease; closed-angle glaucoma; urinary retention due to benign prostatic hyperplasia; pronounced central nervous system (CNS) depression; stroke; acute phase of head injury; gallstones and kidney stones; peptic ulcer of the stomach and duodenum in the period of exacerbation or in history; acute infectious diseases; hypothyroidism, pheochromocytoma, myasthenia, agranulocytosis in history, breastfeeding, comatose state, brain injuries; concomitant use with barbiturates, alcohol, narcotics, dopaminergic antiparkinsonian agents, citalopram, escitalopram.

Interaction with other medicinal products and other types of interactions.

Combinations contraindicated.

With dopaminergic medicinal products (quinagolide, cabergoline), except dopaminergic antiparkinsonian agents – mutual antagonism between the dopaminergic agent and the neuroleptic.

Combinations not recommended.

With dopaminergic antiparkinsonian agents (amantadine, bromocriptine, cabergoline, levodopa, lisuride, pergolide, piribedil, ropinirole) – mutual antagonism between the antiparkinsonian agent and the neuroleptic. Neuroleptic-induced extrapyramidal syndrome should be treated with an anticholinergic agent, but not with a dopaminergic antiparkinsonian agent (dopaminergic receptors blocked by neuroleptics).

With levodopa – mutual antagonism. In patients with Parkinson's disease, minimal doses of each drug are recommended.

With drugs that prolong the QT interval – increased risk of arrhythmias when chlorpromazine is used concomitantly with drugs that prolong the QT interval (including certain antiarrhythmic drugs and other antipsychotic agents, including sulpiride), and drugs causing electrolyte imbalance.

With lithium – high doses of neuroleptics may cause pronounced extrapyramidal symptoms, neurotoxic effects, confusion, hypertension, and hyperreflexia, sometimes with a rapid increase in serum lithium concentration.

With local gastrointestinal agents (magnesium, aluminum, and calcium salts) – reduced absorption of chlorpromazine from the gastrointestinal tract. Do not administer phenothiazine neuroleptics concomitantly with local gastrointestinal agents (if possible, administer with an interval of more than 2 hours between doses).

Combinations requiring cautious use.

With antidiabetic agents – concomitant use of high doses of chlorpromazine (100 mg/day) may lead to increased blood glucose levels (reduced insulin release). The patient should be warned and advised to increase self-monitoring of blood and urine glucose levels. If necessary, adjust the dose of the antidiabetic agent during and after neuroleptic treatment.

With antihypertensive agents – pronounced arterial hypotension, increased orthostatic hypotension. With phenothiazines – enhanced hypotensive effect of anesthetics and calcium channel blockers. Severe postural hypotension may occur when chlorpromazine is taken concomitantly with ACE inhibitors.

With atropine and other atropine derivatives – tricyclic antidepressants, H1-histamine receptor antagonists, anticholinergics, antiparkinsonian agents, atropine-like spasmolytics, disopyramide – increased atropine-related side effects such as urinary retention, constipation, and dry mouth.

With other CNS depressants: morphine derivatives (analgesics, antitussives, and substitution therapy), barbiturates, benzodiazepines, anxiolytics other than benzodiazepines, antihypertensives, ethanol and ethanol-containing preparations – increased CNS depression. Respiratory depression may occur. Changes in attention may make driving or operating machinery hazardous.

Chlorpromazine may reduce the effects of amphetamine, clonidine, guanethidine, and adrenaline.

Anticholinergic agents enhance the anticholinergic effect and may reduce the antipsychotic effect of the drug. Some medicinal products interfere with the absorption of neuroleptics: antacids, antiparkinsonian agents. There are documented clinically significant adverse reactions associated with the use of alcohol, guanethidine, and hypoglycemic agents.

Also, concomitant use with other medicinal products may result in:

with tricyclic antidepressants, maprotiline, or monoamine oxidase inhibitors – prolonged and enhanced sedative and anticholinergic effects, increased risk of developing neuroleptic malignant syndrome;
with anticonvulsant drugs – reduced seizure threshold;
with drugs used to treat hyperthyroidism – increased risk of agranulocytosis;
with drugs causing extrapyramidal reactions – increased frequency and severity of extrapyramidal disturbances;
with ephedrine – reduced vasoconstrictive effect of the latter;
with amphetamines – antagonistic interaction;
with anticholinesterase agents – muscle weakness, worsening of myasthenia;
with epinephrine – reversal of its effects, leading to further reduction in blood pressure and development of severe hypotension and tachycardia;
with amitriptyline – increased risk of tardive dyskinesia, possible development of paralytic ileus;
with diazoxide – pronounced hyperglycemia;
with doxepin – potentiation of hyperpyrexia;
with morphine – development of myoclonus;
with cisapride – additive prolongation of the QT interval on ECG;
with nortriptyline in patients with schizophrenia – possible worsening of clinical condition, despite increased blood levels of chlorpromazine.

The sedative effect of chlorpromazine is enhanced when used concomitantly with zolpidem or zopiclone; the neuroleptic effect – with estrogens. Barbiturates reduce the blood concentration of chlorpromazine (by enhancing its metabolism in the liver). Chloroquine and sulfadoxine/pyrimethamine increase the plasma concentration of chlorpromazine. Cimetidine may either decrease or increase the blood concentration of chlorpromazine.

Chlorpromazine may increase the blood concentration of imipramine, increase or decrease the blood concentration of phenytoin, and reduce the effect of cardiac glycosides.

Special precautions for use.

Use with particular caution in patients with pathological changes in blood parameters, moderate impairment of liver and kidney function, alcohol intoxication, Reye's syndrome, breast cancer, moderate cardiovascular diseases, predisposition to glaucoma, Parkinson's disease, symptomatic benign prostatic hyperplasia, chronic respiratory diseases, epileptic seizures; in conditions associated with an increased risk of thromboembolic complications; in rheumatism, rheumatic carditis, diabetes mellitus; as well as in elderly patients (increased risk of excessive sedative and hypotensive effects) and in debilitated patients.

In case of hyperthermia development, which is one of the symptoms of neuroleptic malignant syndrome, the drug should be discontinued immediately.

To reduce neuroleptic depression, antidepressants and CNS stimulants may be used.

During prolonged treatment with the drug, blood counts, prothrombin index, and liver and kidney function should be monitored regularly.

During therapy, prolonged exposure to sunlight should be avoided due to the possibility of photosensitization of the skin.

The drug does not exhibit antiemetic effect when nausea results from vestibular stimulation or local irritation of the gastrointestinal tract.

When administering the drug to patients with gastrointestinal atony and achylia, it is recommended to co-administer gastric juice or hydrochloric acid (due to chlorpromazine’s inhibitory effect on gastrointestinal motility and gastric secretion), and to monitor diet and intestinal function.

Patients receiving this drug may have an increased requirement for riboflavin.

Neuroleptic phenothiazines may potentiate QT interval prolongation, increasing the risk of ventricular arrhythmias, including torsades de pointes, which may potentially lead to sudden death. Prior to initiating treatment, patients should be evaluated (biochemical status, ECG) to exclude potential risk factors (e.g., cardiac diseases, history of QT prolongation; metabolic disturbances such as hypokalemia, hypocalcemia, hypomagnesemia; starvation, alcohol abuse, concomitant therapy with other drugs that prolong the QT interval). ECG monitoring is required at the beginning of treatment and, if necessary, during treatment.

Use with particular caution in patients with severe arterial hypertension and chronic respiratory diseases (especially in children).

The drug contains lactose. If the patient has known intolerance to certain sugars, medical advice must be sought before taking this medication.

The drug contains the dye sunset yellow FCF (E 110), which may cause allergic reactions.

Use during pregnancy or breastfeeding. The drug is not recommended during pregnancy. If acute necessity for use during pregnancy arises, treatment duration should be limited, and toward the end of the third trimester, the dose should be reduced if possible. Chlorpromazine prolongs labor. High-dose chlorpromazine use during pregnancy has been associated with gastrointestinal disturbances related to its anticholinergic effects and extrapyramidal symptoms in newborns.

If use of the drug is necessary, breastfeeding should be discontinued.

Chlorpromazine and its metabolites cross the placental barrier and are excreted in breast milk.

Ability to influence reaction speed when driving or operating machinery. During treatment, patients should refrain from driving vehicles or operating machinery, and from engaging in potentially hazardous activities requiring high attention and psychomotor speed.

Method of Administration and Dosage

Administer orally to adults and children aged 12 years and older after meals. Dosage, frequency of administration, and treatment regimens are determined individually by a physician depending on the indications and patient's condition. Dosage should be titrated by gradual increases, starting from the minimum effective dose. Duration of treatment ranges from 3 weeks to 2–4 months or longer (patients with chronic disease course should receive long-term maintenance therapy).

For the treatment of psychiatric disorders in adults and children aged 12 years and older, the initial dose is 50–100 mg daily, divided into 1–2 doses. The dose may then be gradually increased (according to tolerability) by 50 mg every 3–4 days up to 300–600 mg daily, divided into 3–4 doses. Treatment duration is from 3 weeks to 2–4 months.

In individual cases, the daily dose may be increased up to 700 mg–1 g (especially in patients with chronic disease course and psychomotor agitation). In such cases, the daily dose should be divided into 4 administrations (morning, afternoon, evening, and night). Treatment with high doses should not exceed 1–1.5 months; if insufficient effect is achieved, switching to other medications is advisable.

Maximum doses: single dose — 300 mg; daily dose — 1.5 g.

Dosage should be reduced 2–3 times in weakened patients, elderly patients, and in patients with liver or cardiovascular diseases (but not exceeding 300 mg daily).

Chronic hiccups. Administer at a dose of 50 mg 3–4 times daily.

Children. In children under 12 years of age, medicinal forms with lower dosage strengths should be used.

Overdose.

Symptoms: slurred speech, unsteady gait, bradycardia, labored breathing, marked weakness, confusion, diminished reflexes, drowsiness, seizures, persistent hypotension, hypothermia, prolonged depression, and later toxic hepatitis.

Treatment: symptomatic therapy. There is no specific antidote. Not removed by hemodialysis. To counteract depression, administer CNS stimulants (sidnocarb). Neurological complications should be reduced or controlled with antiparkinsonian agents (cyclopol, tropacin). In collapse-like states, administration of cordiamine, caffeine, or mesaton is recommended.

After prolonged use of high doses (0.5–1.5 g daily), in isolated cases, jaundice, accelerated blood coagulation, lymphopenia and leukopenia, anemia, agranulocytosis, skin pigmentation, and lens and corneal opacities may occur.

Adverse reactions.

Central nervous system: with prolonged use, akathisia, mental indifference and other psychic changes, delayed response to external stimuli, blurred vision, dystonic extrapyramidal reactions (in the form of acute dystonia, parkinsonian rigidity, tremor or akinesia, and oculogyric crises may develop and spread at moderate or high doses), parkinsonism, dyskinesia, tardive dyskinesia, neuroleptic depression, disturbances of thermoregulation, seizures, insomnia, excitement, anxiety, drowsiness, mood changes, sedation, akathisia, hypertension, torticollis, oculogyric crisis, trismus, akinesia, hyperkinesia.

Cardiovascular system: arterial hypotension, tachycardia, ECG changes (prolongation of QT interval, ST-segment depression, changes in T and U waves, arrhythmia), ventricular tachycardia, ventricular fibrillation, torsade de pointes tachycardia, cardiac arrest, sudden death/sudden cardiac death (with possible cardiac causes, as well as cases of unexplained sudden death in patients receiving phenothiazine neuroleptics), venous embolism, pulmonary embolism (sometimes fatal), deep vein thrombosis, dose-dependent postural hypotension (may occur, particularly in elderly patients and after intramuscular injection), orthostatic hypotension.

Gastrointestinal tract: cholestatic jaundice, liver damage, cholestatic liver injury, mixed liver injury, dyspeptic symptoms (nausea, vomiting), dry mouth, constipation, ischemic colitis, paralytic ileus, intestinal perforation (sometimes fatal), gastrointestinal necrosis (sometimes fatal), intestinal obstruction (sometimes fatal), necrotic colitis.

Hematopoietic system: leukopenia, agranulocytosis, hematological changes, eosinophilia.

Urinary system: difficulty in urination, priapism, urinary retention associated with anticholinergic effect.

Endocrine system: menstrual cycle disturbances, impotence, gynecomastia, weight gain, galactorrhea, hyperprolactinemia, hyperglycemia, impaired glucose tolerance, hypercholesterolemia, hypertriglyceridemia, erectile dysfunction, amenorrhea, female sexual arousal disorders, non-physiological secretion of antidiuretic hormone.

Immune system: hypersensitivity reactions, including skin rashes, pruritus, exfoliative dermatitis, erythema multiforme, urticaria, angioedema, bronchospasm, systemic lupus erythematosus, positive antinuclear antibody test, and other allergic reactions.

Dermatological reactions: skin pigmentation, photosensitization.

Eye disorders: with prolonged use at high doses – deposition of chlorpromazine in anterior eye structures (cornea and lens), which may accelerate the normal aging process of the lens, accommodation disorders.

Respiratory system: nasal congestion.

General: isolated reports of sudden fatal outcome during drug administration, withdrawal syndrome in newborns.

Tardive dyskinesia may occur during or after discontinuation of chlorpromazine and other neuroleptic agents. This syndrome is common among patients who have received moderate to high doses of antipsychotic drugs over prolonged periods and may become irreversible, especially in patients over 50 years of age. It is unlikely in the short term when recommended low or moderate doses of chlorpromazine are used; however, since its occurrence may be related to duration of treatment as well as daily dose, chlorpromazine should be prescribed at the lowest effective dose for the shortest possible duration, except when long-term therapy is required for the treatment of schizophrenia. The potential seriousness and unpredictability of tardive dyskinesia, and the fact that there are rare reports of its development even when neuroleptic antipsychotics have been administered for relatively short periods at low doses, mean that prescribing such agents requires particularly careful assessment of benefit versus risk. Tardive dyskinesia may be accelerated or exacerbated by antiparkinsonian drugs. Short-term dyskinesias may occur after abrupt withdrawal of the drug. In schizophrenia, response to antipsychotic therapy may be delayed. If the drug is discontinued, symptom relapse may not occur for several weeks or months. Neuroleptic malignant syndrome is rare but may occur with any neuroleptic agent.

Chlorpromazine, even at low doses, may cause unpleasant subjective feelings of mental dullness or slowing, nausea, dizziness, headache, or paradoxical effects such as excitement, agitation, or insomnia, particularly in susceptible (especially non-psychotic) individuals. States of confusion or epileptic seizures may occur. The effect of chlorpromazine on the heart is dose-dependent. ECG changes with QT interval prolongation and T-wave abnormalities have usually been reported in patients receiving moderate to high doses; these changes are reversible upon dose reduction. In a small number of cases, such changes have been reported to precede serious arrhythmias, including ventricular tachycardia and fibrillation, occurring after overdose.

Shelf life. 3 years.

Storage conditions. Store in original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. Tablets № 10, № 10×2, № 20 in blisters in a box; № 10 in a blister.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVTYA".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv region, city of Kharkiv, Shevchenko Street, 22.