INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AKTIPROL® (AKTIPROL)

Composition:

Active substance: amisulpride;

One tablet contains 100 mg or 200 mg of amisulpride;

Excipients: lactose monohydrate; sodium starch glycolate (type A); hypromellose 2910 E5; microcrystalline cellulose (PH-101); magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

100 mg tablets: white, round, flat tablets, 9.5 mm in diameter, with an imprint "MC" on one side;

200 mg tablets: white, round, flat tablets, 11.5 mm in diameter, with a break line on one side.

Pharmacotherapeutic group. Psycholeptics. Antipsychotics. Benzamides. Amisulpride. ATC code N05AL05.

Pharmacological properties.

Pharmacodynamics.

Amisulpride is an antipsychotic agent belonging to the class of substituted benzamides. Its pharmacodynamic properties are characterized by selective and predominant affinity for D2 and D3 receptors in the limbic system. Amisulpride has no affinity for serotonin receptors or other neurotransmitter receptors such as histamine, cholinergic, or adrenergic receptors.

In animal studies at high doses, amisulpride predominantly blocks dopaminergic neurons in the mesolimbic system compared to those in the striatal system. This specific receptor affinity explains the favorable antipsychotic effects of amisulpride over its extrapyramidal side effects.

At low doses, amisulpride primarily blocks presynaptic dopaminergic D2 and D3 receptors, which explains its effect on negative symptoms.

In a controlled, double-blind clinical trial comparing amisulpride with haloperidol in 191 patients with acute schizophrenia, amisulpride significantly improved secondary negative symptoms more than haloperidol.

Pharmacokinetics.

In humans, amisulpride exhibits two absorption peaks: the first occurs rapidly, within 1 hour after dosing, and the second occurs 3–4 hours later. Plasma concentration levels after a 50 mg dose are 39 ± 3 and 54 ± 4 ng/mL, respectively.

The volume of distribution is 5.8 L/kg. Plasma protein binding is low (16%), making interactions with other drugs related to protein binding unlikely. Absolute bioavailability is 48%.

Amisulpride undergoes weak metabolism: two inactive metabolites have been identified, accounting for approximately 4% of the administered dose.

Amisulpride does not accumulate in the body, and its pharmacokinetics remain unchanged after repeated dosing. The elimination half-life after oral administration is approximately 12 hours. Amisulpride is excreted unchanged in urine. 50% of an intravenously administered dose is excreted in urine, with 90% of this amount excreted within the first 24 hours. Renal clearance is approximately 330 mL/min. A carbohydrate-rich meal significantly reduces AUC, Tmax, and Cmax of amisulpride, whereas no changes are observed after a high-fat meal. The clinical significance of these changes during amisulpride treatment is unknown.

Hepatic impairment. Since amisulpride undergoes minimal metabolism, dose adjustment is not necessary in patients with hepatic impairment.

Renal impairment. In patients with renal impairment, elimination half-life remains unchanged, while systemic clearance is reduced by 2.5–3 times. AUC of amisulpride is doubled in mild renal impairment and increased nearly 10-fold in moderate renal impairment. Clinical experience is limited, and data for 50 mg doses are lacking. Amisulpride is poorly dialyzable.

Elderly patients. Available pharmacokinetic data in patients aged 65 years and older indicate that after a single 50 mg dose, Cmax, T1/2, and AUC increase by 10–30%. Data on repeated dosing are lacking.

Preclinical safety data. The toxicological profile of amisulpride is defined by the pharmacological effects of the compound. Repeated-dose toxicity studies did not reveal any target organ toxicity. In animal studies, amisulpride affected growth and fetal intrauterine development when administered at doses equivalent to 2000 mg/day or higher for a 50 kg human. There is no evidence indicating that amisulpride has teratogenic potential. No studies on the effects of amisulpride on offspring behavior have been conducted. Carcinogenicity studies showed the development of hormone-dependent tumors in rodents. These findings have no clinical relevance for humans. In animals, reduced fertility was observed, related to the pharmacological properties of the drug (prolactin-mediated effects).

Clinical characteristics.

Indications. Schizophrenia.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Serious episodes of arterial hypertension have been reported in patients with pheochromocytoma who were receiving antidopaminergic agents, including certain benzamides. Therefore, administration of this medicinal product should be avoided in patients with diagnosed or suspected pheochromocytoma.

Age under 15 years (due to lack of clinical data).

Diagnosed or suspected prolactin-dependent tumour, e.g. pituitary prolactinoma or breast cancer (see sections "Special warnings and precautions for use" and "Undesirable effects").

Concomitant use with citalopram, escitalopram, domperidone, hydroxyzine, pimozide, or non-antiparkinsonian dopaminergic agents (cabergoline, quinagolide) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Sedative agents. It should be noted that many medicinal products or substances may cause additive central nervous system depression and contribute to reduced attention. These include morphine derivatives (analgesics, antitussives, and opioid substitution therapy agents), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (e.g. meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-antihistamines, centrally-acting antihypertensives, baclofen, and thalidomide.

Medicinal products capable of inducing torsades de pointes. This serious arrhythmia may be caused by a variety of medicinal products, including antiarrhythmics and others. Contributing factors include hypokalaemia (see subsection "Medicinal products decreasing potassium levels"), bradycardia (see subsection "Medicinal products slowing heart rate"), or pre-existing congenital or acquired QT interval prolongation.

This particularly applies to antiarrhythmic agents of class IA and III, as well as certain neuroleptics. This effect may also be induced by compounds not belonging to these classes.

For dolasetron, erythromycin, spiramycin, and vinpocetine, this interaction applies only to intravenous formulations. In general, concomitant use of a medicinal product that may induce torsades de pointes with another agent having the same effect is contraindicated. However, some of these agents are exceptions, as their use cannot always be avoided, and thus they are simply not recommended for concomitant use with medicinal products that may induce torsades de pointes. This applies to methadone, antiparasitic agents (chloroquine, halofantrine, lumefantrine, pentamidine), and neuroleptics. However, citalopram, escitalopram, domperidone, and hydroxyzine are not included among these exceptions, and their concomitant use with any agent capable of inducing torsades de pointes is contraindicated.

Contraindicated combinations

Dopamine agonists, except antiparkinsonian agonists (cabergoline, quinagolide). Mutual antagonism of effects between dopamine agonists and neuroleptics.

Citalopram, escitalopram, domperidone, hydroxyzine, pimozide. Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Not recommended combinations

Antiparasitic agents capable of inducing torsades de pointes (chloroquine, halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, including torsades de pointes. If possible, one of the two agents should be discontinued. If this combination cannot be avoided, QT interval monitoring before treatment and ECG monitoring are recommended.

Dopaminergic antiparkinsonian agents (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, rasagiline, ropinirole, rotigotine, selegiline, tolcapone). Mutual antagonism of effects between dopamine agonists and neuroleptics. Dopamine agonists may provoke or exacerbate psychotic disorders. When neuroleptic treatment is necessary in a patient with Parkinson's disease receiving dopamine agonists, the dose of dopamine agonists should be gradually reduced and then discontinued (abrupt withdrawal of dopaminergic agents may precipitate neuroleptic malignant syndrome).

Other medicinal products that may induce torsades de pointes: class IA antiarrhythmics (quinidine, hydroquinidine, disopyramide) and class III antiarrhythmics (amiodarone, dronedarone, sotalol, dofetilide, ibutilide), as well as other agents such as arsenic compounds, diphenylthiazine, intravenous dolasetron, intravenous erythromycin, levofloxacin, mequitazine, mizolastine, prucalopride, intravenous vinpocetine, moxifloxacin, intravenous spiramycin, vandetanib, toremifene. Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Other neuroleptics capable of inducing torsades de pointes (chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sulpiride, sultopride, tiapride, zuclopenthixol). Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Alcohol (both in alcoholic beverages and as an excipient). Alcohol enhances the sedative effect of neuroleptics. Reduced attention may make driving and operating machinery hazardous. Consumption of alcoholic beverages and use of medicinal products containing alcohol should be avoided.

Levodopa. Mutual antagonism of effects between levodopa and neuroleptics. Patients with Parkinson's disease should receive the minimum effective doses of each agent.

Methadone. Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Sodium oxybate. Enhanced central nervous system depression. Reduced attention may pose a danger when driving or operating machinery.

Hydroxychloroquine. Increased risk of ventricular arrhythmia, particularly torsades de pointes.

Combinations requiring precautions

Anagrelide. Increased risk of ventricular arrhythmia, particularly torsades de pointes. Clinical and electrocardiographic monitoring are required during concomitant use.

Azithromycin, clarithromycin, ciprofloxacin, levofloxacin, norfloxacin, roxithromycin. Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical and ECG monitoring are required during concomitant use.

Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Increased risk of ventricular arrhythmias, particularly torsades de pointes. In addition, vasodilatory effects and risk of arterial hypotension, especially orthostatic hypotension (additive effect), may occur. Clinical and ECG monitoring are required.

Medicinal products slowing heart rate (especially class IA antiarrhythmics, beta-blockers, certain class III antiarrhythmics, certain calcium channel blockers, digitalis glycosides, pilocarpine, anticholinesterase agents). Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical and ECG monitoring are required.

Medicinal products decreasing potassium levels (potassium-depleting diuretics, alone or in combination, stimulant laxatives, glucocorticoids, tetracosactide, and intravenous amphotericin B). Increased risk of ventricular arrhythmias, particularly torsades de pointes. Any hypokalaemia should be corrected before initiating amisulpride treatment, and clinical status, electrolyte balance, and ECG should be monitored.

Lithium. Risk of neuropsychiatric signs indicating neuroleptic malignant syndrome or lithium toxicity. Regular clinical monitoring and laboratory testing are indicated, especially at the beginning of concomitant therapy.

Ondansetron. Increased risk of ventricular arrhythmia, particularly torsades de pointes. Clinical and electrocardiographic monitoring are required during concomitant use.

Combinations to be taken into account

Other sedative agents. Enhanced central nervous system depression. Impaired ability to concentrate may make driving and operating machinery hazardous.

Orlistat. Risk of reduced therapeutic effect when used concomitantly with orlistat.

Special precautions for use.

Potentially fatal neuroleptic malignant syndrome. As with other neuroleptics, neuroleptic malignant syndrome, which may lead to fatal outcomes, may occur. It is characterized by hyperthermia, muscle rigidity, autonomic dysfunction, impaired consciousness, rhabdomyolysis, and elevated creatine phosphokinase levels. In case of hyperthermia, especially when high doses are used, all antipsychotic agents, including amisulpride, must be discontinued. Rhabdomyolysis has also been observed in patients without neuroleptic malignant syndrome.

QT interval prolongation. Amisulpride may cause dose-dependent prolongation of the QT interval on electrocardiogram, increasing the risk of serious ventricular arrhythmias such as torsades de pointes. The risk of serious ventricular arrhythmias is increased in the presence of bradycardia, hypokalemia, or congenital or acquired prolonged QT interval (e.g., when used concomitantly with drugs that prolong the QTc interval) (see section "Adverse reactions").

If the clinical situation allows, prior to initiating treatment, it is recommended to ensure the absence of factors that may predispose to this arrhythmia, such as:

bradycardia (heart rate < 55 beats/min);
hypokalemia;
congenital prolonged QT interval;
concomitant use of medicinal products that may cause marked bradycardia (< 55 beats/min), hypokalemia, reduced cardiac conduction, or QT interval prolongation (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Electrocardiography (ECG) should be performed before starting treatment in patients requiring long-term neuroleptic therapy.

Stroke. In randomized, placebo-controlled clinical trials involving elderly patients with dementia treated with certain atypical antipsychotics, the risk of stroke was approximately three times higher than in the placebo group. The mechanism underlying this increased risk is unknown. An increased risk associated with other antipsychotics and risk in other patient populations cannot be ruled out. This medicinal product should be used with caution in patients with risk factors for stroke.

Elderly patients with dementia. The risk of fatal outcome is increased in elderly patients with psychosis associated with dementia who are treated with antipsychotic agents. Analysis of 17 placebo-controlled clinical trials (mean duration – 10 weeks), conducted in patients primarily receiving atypical antipsychotics, showed that patients treated with these medicinal products had a 1.6- to 1.7-fold higher risk of fatal outcome compared to those receiving placebo. After treatment lasting on average 10 weeks, the risk of fatal outcome was 4.5% in the antipsychotic group compared to 2.6% in the placebo group.

Although the causes of fatal outcomes in clinical trials with atypical antipsychotics were varied, most deaths were due to either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) causes.

Observational studies suggest that traditional antipsychotics may also increase mortality, similar to atypical antipsychotics.

The relative contribution of antipsychotic agents and patient-specific factors to increased mortality in epidemiological studies remains unclear.

Venous thromboembolism (VTE). Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic agents. Since patients treated with antipsychotics often have acquired risk factors for VTE, potential risk factors for VTE should be identified before initiating treatment with Actiprol® or during such treatment, and preventive measures should be taken (see section "Adverse reactions").

Hyperglycemia/metabolic syndrome. Cases of hyperglycemia or impaired glucose tolerance, and development or worsening of diabetes mellitus, have been reported in patients treated with certain antipsychotic agents, including amisulpride (see section "Adverse reactions").

According to current guidelines, clinical and laboratory monitoring of patients receiving Actiprol® treatment is required. Particular attention should be paid to patients with diabetes mellitus or risk factors for its development.

Seizures. Amisulpride may lower the seizure threshold. Therefore, patients with a history of seizures should be closely monitored during therapy with amisulpride.

Special patient groups. Since amisulpride is eliminated via the kidneys, the dose should be reduced or alternative treatment considered in patients with renal impairment (see section "Dosage and administration"). There are no data available for patients with severe renal impairment (see section "Dosage and administration").

As with other antipsychotic agents, amisulpride should be used with particular caution in elderly patients due to the potential risk of sedation and arterial hypotension. Elderly patients may also require dose reduction due to renal impairment (see section "Dosage and administration").

As with other antidopaminergic agents, caution is required when prescribing amisulpride to patients with Parkinson's disease, as it may worsen the condition. Amisulpride should be used only if treatment with neuroleptics cannot be avoided.

Withdrawal syndrome. Withdrawal symptoms, including nausea, vomiting, and insomnia, have been described following abrupt discontinuation of antipsychotics used at high doses. Cases of psychotic symptom relapse and emergence of involuntary movement disorders (such as akathisia, dystonia, and dyskinesia) have been reported with amisulpride. Therefore, gradual discontinuation of amisulpride is recommended.

Hyperprolactinemia. Amisulpride may increase prolactin levels (see section "Adverse reactions"). Patients with hyperprolactinemia and/or potentially prolactin-dependent tumors should be closely monitored during treatment with amisulpride (see section "Contraindications").

Benign pituitary tumor. Amisulpride may increase prolactin levels. Cases of benign pituitary tumors, such as prolactinoma, have been reported during treatment with amisulpride (see section "Adverse reactions"). In cases of very high prolactin levels or clinical signs suggestive of a pituitary tumor (e.g., visual field defects, headache), imaging studies should be performed to evaluate the pituitary gland. If a pituitary tumor is confirmed, treatment with amisulpride must be discontinued (see section "Contraindications").

Hepatotoxicity. Severe hepatotoxic reactions have been reported during treatment with amisulpride. Patients should be informed that if any signs of liver injury occur, such as asthenia, anorexia, nausea, vomiting, abdominal pain, or jaundice, they should seek immediate medical attention. Prompt evaluation, including clinical assessment and liver function tests, should be performed (see section "Adverse reactions").

Other. Leukopenia, neutropenia, and agranulocytosis have been reported during treatment with antipsychotics, including amisulpride (see section "Adverse reactions"). Fever or infections of unknown etiology may indicate leukopenia and require immediate hematological investigation.

This medicinal product is not recommended for use in combination with alcohol, dopaminergic anti-Parkinson agents, antiparasitic agents capable of provoking torsades de pointes, methadone, levodopa, other neuroleptics, or medicinal products capable of provoking torsades de pointes, sodium oxybate, or hydroxychloroquine (see section "Interaction with other medicinal products and other forms of interaction").

Precautions related to excipients. This medicinal product contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy. Data on the use of amisulpride in pregnant women are limited. Therefore, the safety of amisulpride during pregnancy has not been established. Amisulpride crosses the placenta. Animal studies have shown reproductive toxicity (see subsection "Preclinical safety data"). Use of amisulpride during pregnancy is not recommended, except when the benefit outweighs the potential risk.

Newborns whose mothers received antipsychotics (including amisulpride) during the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms of varying severity and duration after birth (see section "Adverse reactions"). Adverse reactions such as agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress syndrome, or feeding difficulties have been reported. Therefore, careful monitoring of newborns is required.

Breastfeeding. Amisulpride is excreted in breast milk in considerable amounts, in some cases exceeding 10% of the maternal dose adjusted for body weight. There are no data on amisulpride concentrations in infant blood. Information on the effects of amisulpride on neonates/infants is insufficient. The benefit of breastfeeding for the infant and the benefit of amisulpride treatment for the mother should be weighed, and a decision made whether to discontinue breastfeeding or to discontinue amisulpride therapy.

Fertility. In animal studies, reduced fertility associated with the pharmacological effects of the drug (prolactin-mediated effect) has been observed.

Ability to affect reaction speed when driving or operating machinery. Patients, especially those who drive or operate machinery, should be warned of the risk of somnolence or blurred vision associated with the use of this medicinal product (see section "Adverse reactions").

Method of Administration and Dosage

If the daily dose does not exceed 400 mg, the drug should be taken once daily. Doses exceeding 400 mg per day should be divided into two administrations.

Acute psychotic episodes. Treatment may be initiated with intramuscular administration of the drug in the appropriate dosage form for several days, at a maximum dose of 400 mg/day, followed by transition to oral administration. Doses from 400 mg/day to 800 mg/day are recommended to be administered orally. The maximum oral dose must never exceed 1200 mg/day. The safety of doses exceeding 1200 mg/day has not been widely studied. Therefore, such doses should not be used.

The maintenance dose or dose adjustment must be individually determined according to the patient's response. In all cases, maintenance therapy should be individually prescribed at the lowest effective dose.

Predominantly negative episodes. Recommended doses range from 50 mg/day to 300 mg/day. Doses should be individually titrated. The optimal dose is approximately 100 mg/day.

Children. The efficacy and safety of amisulpride in children and adolescents from puberty up to the age of 18 years have not been established: data on the use of amisulpride in children (under 18 years of age) with schizophrenia are limited. For this reason, the use of amisulpride in children and adolescents from puberty up to 18 years of age is not recommended. Amisulpride is contraindicated in children under 15 years of age, as the safety of this medicinal product in this patient population has not yet been established (see section "Contraindications").

Geriatric patients. The safety of amisulpride in elderly patients has been evaluated in a limited number of cases. This medicinal product should be used with particular caution in this patient subgroup due to the risk of arterial hypotension and sedative effects. Dose reduction may also be required for patients with renal impairment (see section "Special Warnings and Precautions for Use").

Renal impairment. Since amisulpride is eliminated via the kidneys, the daily dose should be halved in patients with creatinine clearance of 30–60 mL/min, and reduced to one-third in patients with creatinine clearance of 10–30 mL/min. Due to insufficient data in patients with severe renal impairment (creatinine clearance < 10 mL/min), strict monitoring of such patients is recommended (see section "Special Warnings and Precautions for Use").

Hepatic impairment. Since the drug is weakly metabolized, dose reduction is not required.

Children. The efficacy and safety of amisulpride in children and adolescents from puberty up to the age of 18 years have not been established: data on the use of amisulpride in children under 18 years of age with schizophrenia are limited. Therefore, the use of amisulpride in this patient population is not recommended. Amisulpride is contraindicated in children under 15 years of age, as the safety of this medicinal product in such patients has not yet been established (see section "Contraindications").

Overdose.

Currently, data regarding acute amisulpride overdose are limited. Reported signs and symptoms are mainly due to enhanced pharmacological activity, clinically manifesting as somnolence, sedation, coma, arterial hypotension, and extrapyramidal symptoms. Fatal cases have been reported, primarily in association with concomitant use of other psychotropic agents.

There is no known specific antidote for amisulpride. In case of acute overdose, it is essential to determine whether other medicinal products have been co-ingested and to take appropriate measures:

careful monitoring of vital functions;
cardiac monitoring (risk of QT interval prolongation) until full recovery of the patient;
in case of severe extrapyramidal symptoms, anticholinergic agents should be administered;
since amisulpride is poorly dialyzable, the effectiveness of hemodialysis for elimination of this medicinal compound is limited.

Adverse Reactions

Adverse effects are classified by frequency according to the following scale: 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 (cannot be estimated from the available data).

Nervous system disorders.
Very common: extrapyramidal symptoms (tremor, hypertonia, hypersalivation, akathisia, hypokinesia, dyskinesia). In most cases, these are mild in severity at optimal doses and are partially reversible without discontinuation of amisulpride when anticholinergic anti-Parkinson agents are administered.

The frequency of extrapyramidal symptoms, which is dose-dependent, is very low in patients receiving doses of 50–300 mg/day for predominantly negative symptoms.

Common: acute dystonia (spasmodic torticollis, oculogyric crisis, trismus), which is reversible without discontinuation of amisulpride when an anticholinergic anti-Parkinson agent is administered. Somnolence.

Uncommon: tardive dyskinesia characterized by involuntary movements of the tongue and/or facial muscles, usually after long-term treatment. Anticholinergic anti-Parkinson agents are ineffective or may worsen symptoms. Seizures.

Rare: neuroleptic malignant syndrome, which may be fatal (see section "Special precautions for use").

Frequency not known: restless legs syndrome.

Psychiatric disorders.
Common: insomnia, anxiety, agitation, frigidity.
Uncommon: confusion.

Gastrointestinal disorders.
Common: constipation, nausea, vomiting, dry mouth.

Endocrine disorders.
Common: increased plasma prolactin levels, reversible after discontinuation of the drug. This may lead to the following clinical symptoms: galactorrhea, amenorrhea, gynecomastia, breast pain, erectile dysfunction.

Rare: benign pituitary tumour, such as prolactinoma (see sections "Contraindications" and "Special precautions for use").

Metabolism and nutrition disorders.
Uncommon: hyperglycaemia (see section "Special precautions for use"), hypertriglyceridaemia, hypercholesterolaemia.

Rare: hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Cardiac disorders.
Uncommon: bradycardia.

Rare: QT interval prolongation, ventricular arrhythmias such as torsades de pointes, ventricular tachycardia, which may lead to ventricular fibrillation or cardiac arrest, sudden death (see section "Special precautions for use").

Respiratory, thoracic and mediastinal disorders.
Uncommon: nasal congestion, aspiration pneumonia (mainly when other antipsychotics and CNS depressants are used concomitantly).

Investigations.
Common: weight increased.
Uncommon: elevated liver enzymes, predominantly transaminases.
Frequency not known: increased blood creatine phosphokinase levels.

Immune system disorders.
Uncommon: allergic reactions.

Eye disorders.
Common: blurred vision (see section "Ability to influence driving and use of machinery").

Hepatobiliary disorders.
Uncommon: hepatocellular injury.

Skin and subcutaneous tissue disorders.
Rare: angioneurotic oedema, urticaria.
Frequency not known: photosensitivity reaction.

Musculoskeletal and general disorders.
Uncommon: osteopenia, osteoporosis.
Frequency not known: rhabdomyolysis.

Renal and urinary disorders.
Uncommon: urinary retention.

Injury, poisoning and procedural complications.
Frequency not known: falls due to adverse reactions leading to impaired body balance.

Blood and lymphatic system disorders.
Uncommon: leukopenia, neutropenia (see section "Special precautions for use").
Rare: agranulocytosis (see section "Special precautions for use").

Vascular disorders.
Common: arterial hypotension.
Uncommon: increased blood pressure.
Rare: cases of venous thromboembolism, including pulmonary embolism (sometimes fatal), and deep vein thrombosis have been reported with antipsychotic drugs (see section "Special precautions for use").

Pregnancy, puerperium and perinatal conditions.
Frequency not known: withdrawal syndrome in newborns (see section "Use during pregnancy or breastfeeding").

Reporting of adverse reactions.
Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Medocemie Limited / Medochemie Limited.

Manufacturer's address and location of operations.
Konstantinoupoleos 1-10, Limassol, 3011, Cyprus / Konstantinoupoleos 1-10, Limassol, 3011, Cyprus.