Instructions for Solex tablets 200 mg blister No. 30
Composition
active ingredient: amisulpride;
1 tablet contains amisulpride 100 mg or 200 mg;
Excipients: lactose monohydrate; microcrystalline cellulose; methylcellulose; sodium starch glycolate (type A); magnesium stearate.
Dosage form
Pills.
Main physicochemical properties:
100 mg tablets: white or almost white, round, flat tablets with a diameter of approximately
8.0 mm, with a score line on one side and embossed A100 on the other side;
200 mg tablets: white or almost white, round, flat tablets with a diameter of approximately 11.0 mm, with a score line on one side and embossed A200 on the other side.
Pharmacotherapeutic group
Antipsychotics. ATX code N05A L05.
Pharmacological properties
Pharmacodynamics.
Its pharmacodynamic properties are characterized by selective and predominant affinity for D2 and D3 receptors of the limbic system, while not having affinity for the D1 D4 and D5 subtypes. Amisulpride has no affinity for serotonin receptors and other neuroreceptors, such as histamine H1 receptors, cholinergic and adrenergic receptors. In addition, amisulpride does not bind to sigma sites. In animal studies at high doses, amisulpride blocks predominantly dopaminergic neurons of the mesolimbic system compared to the same ones of the striatal system. At low doses, amisulpride blocks predominantly presynaptic dopaminergic D2 and D3 receptors, which explains its effect on negative symptoms. This pharmacological profile explains the clinical efficacy of Solex® against both negative and positive symptoms of schizophrenia.
Pharmacokinetics.
In humans, amisulpride shows two absorption maxima: the first occurs rapidly, 1 hour after dosing, and the second occurs 3–4 hours later.
The corresponding plasma concentrations after a 50 mg dose are 39 ± 3 and 54 ± 4 ng/ml.
The volume of distribution is 5.8 l/kg, plasma protein binding is low (16%), protein-bound interactions with other drugs are unlikely. Absolute bioavailability is 48%.
Amisulpride is poorly metabolized: two inactive metabolites have been identified, accounting for about 4% of the total amount of the drug administered.
Amisulpride does not accumulate in the body, and its pharmacokinetics remain unchanged after repeated doses.
The half-life after an oral dose is approximately 12 hours.
Amisulpride is excreted unchanged in the urine.
Renal clearance is approximately 20 L/h or 330 mL/min.
A carbohydrate-rich meal (containing 68% liquid) significantly reduces the AUC, Tmax, Cmax of amisulpride, while no changes are observed after a fatty meal. The effect of these changes during treatment with amisulpride is unknown.
Liver failure.
Since amisulpride is poorly metabolized, there is no need to reduce the dose for patients with hepatic insufficiency.
Kidney failure.
In patients with renal insufficiency, the half-life does not change, while systemic clearance is reduced by 2.5–3 times.
The AUC of amisulpride increases twofold in mild renal failure, and almost 10-fold in moderate renal failure.
Practical experience, however, is limited and there are no data on doses exceeding 50 mg.
Amisulpride is dialyzed very poorly.
Elderly patients.
Available pharmacokinetic data in patients aged 65 years and older indicate that after a single dose of 50 mg Cmax, T1/2 and AUC increase by 10-30%. Data on repeated doses are not available.
Indication
Treatment of schizophrenia.
Contraindication
Hypersensitivity to the active substance or to any other component of the medicinal product.
Serious episodes of hypertension have been reported in patients with pheochromocytoma receiving antidopaminergic drugs, including some benzamides. It is advisable to refrain from prescribing this drug to patients with diagnosed or suspected pheochromocytoma who are receiving antidopaminergic drugs, including some benzamides.
Known or suspected prolactin-dependent tumors, such as prolactin-secreting pituitary adenoma and breast cancer.
In combination with mecitazine, citalopram, escitalopram, domperidone, hydroxyzine, non-antiparkinsonian dopaminergic drugs (cabergoline, quinagolide). Use in combination with levodopa (see section "Interaction with other medicinal products and other types of interactions").
Children under 15 years of age (due to lack of clinical data).
Combination with medicinal products that may cause torsades de pointes (see section “Interaction with other medicinal products and other types of interactions”).
Interaction with other medicinal products and other types of interactions
Sedatives. It should be noted that many drugs or substances can cause additive central nervous system (CNS) depressant effects and contribute to decreased alertness. These include morphine derivatives (analgesics, antitussives and substitution treatments), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (such as meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-antihistamines, centrally acting antihypertensives, baclofen and thalidomide.
Drugs that can cause torsades de pointes. This serious arrhythmia can be caused by a number of drugs, such as antiarrhythmics and other drugs. Predisposing factors include hypokalemia (see section “Potassium-lowering drugs”), bradycardia (see section “Heart rate-slowing drugs”), or pre-existing congenital or acquired QT prolongation.
This is particularly true for class IA and III antiarrhythmics and some neuroleptics. This effect is also induced by other compounds that do not belong to these classes.
For dolasetron, erythromycin, spiramycin and vincamine, this interaction only applies to intravenous dosage forms.
In general, the use of a drug that causes torsades de pointes with another drug that has the same effect is contraindicated.
However, some of these drugs are exceptions, as their use cannot be avoided and therefore they are simply not recommended for use in combination with drugs that can induce torsades de pointes. This applies to methadone, antiparasitic drugs (halofantrine, lumefantrine, pentamidine) and neuroleptics.
However, these exceptions do not include citalopram, escitalopram, domperidone, and hydroxyzine, and therefore their use with all drugs that can induce torsades de pointes is contraindicated.
Contraindicated combinations (see section "Contraindications").
Dopamine agonists, except antiparkinsonian agonists (cabergoline, quinagolide, rotigotine). Mutual antagonism of the effects of dopamine agonists and neuroleptics.
Citalopram, escitalopram, domperidone, hydroxyzine. Increased risk of ventricular arrhythmias, especially torsades de pointes.
Mechitazine: Increased risk of ventricular arrhythmias, especially torsades de pointes.
Not recommended combinations (see section "Special instructions for use")
Antiparasitic drugs that can cause torsades de pointes (chloroquine, halofantrine, lumefantrine, pentamidine). Increased risk of ventricular arrhythmias, including torsades de pointes. If possible, treatment with one of the two drugs should be discontinued. If this combination cannot be avoided, pre-treatment QT monitoring and ECG monitoring are recommended.
Dopaminergic antiparkinsonian drugs (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, rasagiline, ropinirole, rotigotine, selegiline, tolcapone). Mutual antagonism of the effects of dopamine agonists and neuroleptics. Dopamine agonists can provoke or exacerbate psychotic disorders. When the use of a neuroleptic is necessary for a patient suffering from Parkinson's disease and taking dopamine agonists, it is necessary to gradually reduce the dose of dopamine agonists, and then discontinue the drug (abrupt withdrawal of dopaminergic drugs threatens the development of neuroleptic malignant syndrome).
Other drugs 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 drugs such as arsenic compounds, bepridil, cisapride, diphemanil, dolasetron intravenously, domperidone, erythromycin intravenously, levofloxacin, mehitazine, mizolastine, prucalopride, vincamine intravenously, moxifloxacin, sparfloxacin, spiramycin intravenously, thioridazine, vandetanib, toremifene. Increased risk of ventricular arrhythmias, including torsades de pointes.
Other neuroleptics that can induce torsades de pointes (chlorpromazine, cyamemazine, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperon, pipotiazine, sertindole, sulpiride, sultopride, tiapride, zuclopenthixol). Increased risk of ventricular arrhythmias, including torsades de pointes.
Alcohol consumption. Alcohol enhances the sedative effect of neuroleptics. Amisulpride may enhance the effects of alcohol on the CNS. Reduced alertness may make driving and operating machinery dangerous. Alcoholic beverages and medications containing alcohol should be avoided.
Levodopa. Mutual antagonism of the effects of levodopa and neuroleptics. Patients with Parkinson's disease should use the minimum effective doses of each of these drugs.
Methadone: Increased risk of ventricular arrhythmias, including torsades de pointes.
Sodium oxybutyrate. Increased CNS depression. Reduced attention may lead to danger when driving vehicles and operating other mechanisms.
Combinations requiring precautions.
Azithromycin, clarithromycin, ciprofloxacin, levofloxacin, norfloxacin, roxithromycin. Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and ECG monitoring is necessary when these drugs are used concomitantly.
Beta-blockers in patients with heart failure (bisoprolol, carvedilol, metoprolol, nebivolol). Increased risk of ventricular arrhythmias, especially torsades de pointes. In addition, there is a vasodilator effect and a risk of arterial hypotension, especially orthostatic (additive effect). Clinical and ECG monitoring is necessary.
Drugs that slow the heart rate (especially class IA antiarrhythmics, beta-blockers, some class III antiarrhythmics, some calcium channel blockers, digitalis, pilocarpine, anticholinesterase drugs). Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and ECG monitoring is necessary.
Drugs that lower potassium levels (potassium-sparing diuretics, alone or in combination, stimulant laxatives, glucocorticoids, tetracosactides and intravenous amphotericin B). Increased risk of ventricular arrhythmias, including torsades de pointes. Any hypokalemia should be corrected before starting treatment with amisulpride and clinical, electrolyte and ECG monitoring should be performed.
Lithium: Risk of neuropsychiatric signs suggestive of neuroleptic malignant syndrome or lithium toxicity. Regular clinical and laboratory monitoring is indicated, especially at the beginning of concomitant use.
Ondansetron: Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and electrocardiographic monitoring is required during concomitant use of this drug.
Roxithromycin: Increased risk of ventricular arrhythmias, especially torsades de pointes. Clinical and ECG monitoring is necessary when these drugs are used concomitantly.
Combinations to consider.
Other sedatives. Increases central nervous system depression. Impaired ability to concentrate may make driving and operating machinery dangerous.
Antihypertensives: Increased risk of hypotension, particularly postural hypotension.
Nitrate derivatives and related substances: Increased risk of arterial hypotension, particularly postural hypotension.
Orlistat. Risk of reduced therapeutic effect with concomitant use of orlistat.
Application features
Special warnings.
Neuroleptic malignant syndrome.
As with other neuroleptics, neuroleptic malignant syndrome, which can be fatal, is characterized by hyperthermia, muscle rigidity, peripheral nervous system dysfunction, impaired consciousness, and increased CPK levels. If hyperthermia develops, especially when using high doses, all antipsychotic drugs should be discontinued.
QT interval prolongation.
Solex® may cause dose-dependent prolongation of the QT interval on the electrocardiogram, which increases the risk of serious ventricular arrhythmias such as torsades de pointes.
The risk of serious ventricular arrhythmias increases in bradycardia, hypokalemia, in case of congenital or acquired prolonged QT interval (combination with drugs that prolong the QT interval) (see section "Adverse reactions").
If the clinical situation allows, before using the drug it is recommended to make sure that there are no factors that may contribute to the development of this rhythm disorder, such as, for example:
bradycardia less than 55 beats/min;
electrolyte imbalance, including hypokalemia;
congenital prolonged QT interval;
use of drugs that can cause severe bradycardia (< 55 beats/min), hypokalemia, decreased cardiac conduction or prolongation of the QT interval (see section "Contraindications").
Patients who require long-term treatment with neuroleptics should have an ECG performed before starting treatment.
Cerebral stroke.
In randomized, placebo-controlled clinical trials in elderly patients with dementia treated with some atypical antipsychotics, an increased risk of stroke was observed compared to placebo.
The mechanism underlying this increased risk is unknown. An increased risk associated with other antipsychotics and the presence of a risk in other patient populations cannot be excluded. This drug should be used with caution in patients with risk factors for stroke.
Elderly patients with dementia.
The risk of death is increased in elderly patients with dementia-related psychosis who are taking antipsychotics.
An analysis of 17 placebo-controlled clinical trials (average duration – 10 weeks) conducted among patients taking mainly atypical antipsychotics showed that compared with placebo, the risk of death in patients treated with these drugs increased by 1.6–1.7 times.
Although the causes of death during clinical trials with atypical antipsychotics varied, the majority of deaths were due to either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) causes.
Epidemiological studies show that traditional antipsychotics may increase mortality, as is the case with atypical antipsychotics.
The respective role of antipsychotics and individual patient characteristics in increasing mortality in epidemiological studies remains unknown. Solex® is not licensed for the treatment of dementia-related behavioral disorders.
Venous thromboembolism.
Cases of venous thromboembolism (VTE), sometimes fatal, have been reported with antipsychotics. Since patients treated with antipsychotics often have acquired risk factors for VTE, possible risk factors for VTE should be identified before initiating treatment with Solex® or during such treatment and preventive measures should be taken (see section 4.8).
Hyperglycemia/metabolic syndrome.
Cases of hyperglycemia have been reported in patients treated with some antipsychotics, including amisulpride (see section 4.8).
Clinical and laboratory monitoring should be performed in accordance with current guidelines in patients receiving treatment with Solex®. Particular attention should be paid to patients with diabetes mellitus or with factors predisposing to diabetes.
Convulsions.
Amisulpride may lower the seizure threshold. Therefore, patients with a history of seizures require careful monitoring during amisulpride therapy.
Special patient groups.
Since amisulpride is eliminated by the kidneys, the dose should be reduced or alternative treatment should be considered in patients with renal impairment (see section 4.2). There are no data in patients with severe renal impairment (see section 4.2).
As with other antipsychotics, amisulpride should be used with particular caution in elderly patients due to the possible risk of sedation and hypotension. Dosage reduction may also be necessary due to renal insufficiency.
As with other antidopaminergic agents, caution should be exercised when prescribing amisulpride to patients with Parkinson's disease, as it may worsen the disease. Amisulpride should only be used when neuroleptic treatment cannot be avoided.
Withdrawal syndrome.
Withdrawal symptoms have been described after abrupt discontinuation of high doses of antipsychotics, including nausea, vomiting and insomnia, and have been very rarely described after abrupt discontinuation of high doses of antipsychotics. Recurrence of psychotic symptoms may also occur. Involuntary movement disorders (such as akathisia, dystonia and dyskinesia) have been reported with amisulpride. Therefore, gradual discontinuation of amisulpride is advisable.
It is not recommended to use this medicine in combination with alcohol, dopaminergic antiparkinsonian agents, antiparasitic agents that can provoke torsades de pointes; with methadone, levodopa, other neuroleptics or drugs that can provoke torsades de pointes (see section "Interaction with other medicinal products and other types of interactions").
Hyperprolactinemia: Amisulpride may increase prolactin levels (see section 4.8). Patients with hyperprolactinemia and/or potentially prolactin-dependent tumors should be closely monitored during treatment with amisulpride (see section 4.3).
Precautions related to excipients.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance (galactosemia), the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Breast cancer.
Solex® may increase prolactin levels. Therefore, amisulpride should be prescribed with caution to patients with a personal or family history of breast cancer, and close monitoring is necessary during therapy with this drug.
Benign pituitary tumor.
Amisulpride may increase prolactin levels. Cases of benign pituitary tumors, such as prolactinoma, have been observed during amisulpride therapy (see section "Adverse reactions"). In the event of very high prolactin levels or clinical signs of a pituitary tumor (such as visual field defect and headache), imaging of the pituitary gland should be performed. If the diagnosis of a pituitary tumor is confirmed, amisulpride treatment should be discontinued (see section "Contraindications").
Others
Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including Solex®. Fever or unexplained infection may indicate leukopenia (see section 4.8) and require immediate haematological evaluation.
Severe liver toxicity has been reported with amisulpride. Patients should be instructed to report symptoms such as asthenia, anorexia, nausea, vomiting, abdominal pain or jaundice to their physician immediately. Investigations, including clinical examination and biological evaluation of liver function, should be performed promptly (see section 4.8).
Use during pregnancy or breastfeeding
Pregnancy
Animal studies have shown reproductive toxicity of Amisulpride. Amisulpride crosses the placenta.
Clinical data on use in pregnancy are limited. Accordingly, the safety of amisulpride during pregnancy has not been established. Amisulpride is not recommended during pregnancy unless the benefits justify the potential risks.
If the drug is used during pregnancy, the newborn may experience side effects of amisulpride. During the third trimester of pregnancy, there is a risk of adverse reactions such as extrapyramidal syndromes and/or withdrawal syndrome, which may vary in severity and duration after delivery. Adverse reactions such as agitation, hypertonia, hypotension, tremor, drowsiness, respiratory distress syndrome or difficulty feeding have been reported. Therefore, close monitoring of the newborn is necessary.
Fertility
A decrease in fertility was observed, associated with the pharmacological effects of the drug (prolactin-mediated effect).
Breast-feeding.
Due to the lack of information on the penetration of amisulpride into breast milk, breastfeeding is contraindicated.
Ability to influence reaction speed when driving vehicles or other mechanisms
Patients, especially those who drive and operate machinery, should be warned about the risk of drowsiness and blurred vision when taking this medicine (see section "Adverse reactions").
Method of administration and doses
If the daily dose does not exceed 400 mg, the drug should be taken once a day.
Doses above 400 mg should be divided into 2 doses per day.
Acute psychotic episodes.
Treatment can be initiated with intramuscular administration, which will last for several days, at a maximum dose of 400 mg/day, followed by a transition to oral administration.
Doses of 400 mg/day to 800 mg/day are recommended orally. The maximum oral dose should not exceed 1200 mg/day. The safety of doses above 1200 mg/day has not been extensively studied. Therefore, such doses should not be used.
The maintenance dose or dose adjustment should be individualized according to the patient's response.
In all cases, maintenance therapy should be prescribed individually, at the minimum effective dose.
Mostly negative episodes.
Recommended doses range from 50 mg/day to 300 mg/day. Doses should be adjusted individually. The optimal dose is about 100 mg/day.
Elderly patients.
Amisulpride should be used with particular caution in this population due to the risk of hypotension and sedation (see section 4.3). A dose reduction may also be required in patients with renal impairment.
Kidney failure.
Since amisulpride is excreted by the kidneys, in renal failure with creatinine clearance 30-60 ml/min the daily dose should be reduced by half, and in renal failure with creatinine clearance 10-30 ml/min - by a third. Due to insufficient data in patients with severe renal failure (CC < 10 ml/min), close monitoring of such patients is recommended (see section "Contraindications").
Liver dysfunction.
Since the drug is poorly metabolized, dose reduction is not required.
Children.
The efficacy and safety of amisulpride in children from puberty to 18 years of age have not been established; data on the use of amisulpride in children with schizophrenia are limited. For this reason, the use of amisulpride in children from puberty to 18 years of age is not recommended. Amisulpride is contraindicated in children under 15 years of age due to the lack of clinical data.
Overdose
There is currently limited data on acute overdose of amisulpride. The symptoms reported are mainly the result of increased pharmacological activity, clinically manifested by dizziness, sedation, coma, hypotension and extrapyramidal symptoms.
There have been reports of fatal outcomes when used concomitantly with other psychotropic drugs.
There is no specific antidote for amisulpride. In the event of acute overdose, it should be determined whether another drug has been used concomitantly and appropriate measures should be taken:
careful monitoring of vital functions;
monitoring of cardiac activity (risk of QT interval prolongation) until the patient recovers completely;
in case of severe extrapyramidal symptoms, anticholinergics should be prescribed;
Since amisulpride is poorly dialyzable, the possibilities of hemodialysis for the removal of this drug compound are limited.
Side effects
Adverse reactions 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 unknown (cannot be estimated from the available data).
From the nervous system.
Very common: extrapyramidal symptoms (tremor, rigidity, hypertonia, increased salivation, akathisia, hypokinesia, dyskinesia) may occur. In most cases, they are mild at maintenance doses and partially reversible without discontinuation of amisulpride when anticholinergic antiparkinsonian agents are administered.
The dose-dependent incidence of extrapyramidal symptoms is very low in patients treated for predominantly negative symptoms with doses of 50–300 mg/day.
Common: drowsiness, possible acute dystonia (spastic torticollis, oculogyric crisis, trismus). It is reversible without discontinuation of amisulpride when an anticholinergic antiparkinsonian agent is prescribed.
Uncommon: Tardive dyskinesia, characterised by involuntary movements of the tongue and/or facial muscles, has been reported, usually after long-term use of the drug.
Anticholinergic antiparkinsonian drugs are ineffective or may cause worsening of symptoms.
Convulsions.
Rare: neuroleptic malignant syndrome, which is a potentially fatal complication.
Not known: restless legs syndrome.
Mental disorders
Common: insomnia, anxiety, agitation, frigidity.
Uncommon: confusion.
From the digestive system.
Common: constipation, nausea, vomiting, dry mouth.
From the endocrine system.
Common: Increased plasma prolactin levels, reversible upon discontinuation of the drug. This may cause the following clinical symptoms: galactorrhea, amenorrhea, gynecomastia, breast pain, erectile dysfunction.
Rare: benign pituitary tumor such as prolactinoma (see sections "Contraindications" and "Special warnings and precautions for use").
From the side of metabolism and nutrition.
Common: hyperglycemia (see section "Special warnings and precautions for use"), hypertriglyceridemia and hypercholesterolemia.
Rare: hyponatremia, syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Laboratory studies.
Common: weight gain.
Uncommon: Elevated liver enzymes, mainly transaminases, have been reported.
From the immune system.
Uncommon: allergic reactions.
From the cardiovascular system.
Common: bradycardia.
Rare:
QT interval prolongation;
ventricular arrhythmias such as torsades de pointes and ventricular tachycardia, which can lead to ventricular fibrillation and cardiac arrest;
sudden death (see section "Special warnings and precautions for use").
Vascular disorders.
Common: hypotension.
Uncommon: increased blood pressure.
Rare: Cases of venous thromboembolism, including pulmonary embolism, sometimes fatal, and deep vein thrombosis have been reported with the use of antipsychotics (see section 4.4).
From the blood and lymphatic system.
Uncommon: leukopenia, neutropenia.
Rare: agranulocytosis (see section "Special warnings and precautions for use").
On the skin and subcutaneous tissue.
Rare: angioedema, urticaria.
Not known: photosensitivity reaction.
Pathological conditions during pregnancy, postpartum and perinatal periods.
Frequency not known: withdrawal syndrome in newborns (see section "Use during pregnancy or breastfeeding").
Musculoskeletal and connective tissue disorders.
Uncommon: osteopenia, osteoporosis.
On the part of the kidneys and urinary tract.
Uncommon: urinary retention.
From the liver and biliary tract.
Uncommon: hepatocellular damage.
Respiratory, thoracic, and mediastinal disorders.
Uncommon: nasal congestion, aspiration pneumonia (mainly in combination with other neuroleptics and CNS depressants).
From the organs of vision.
Common: blurred vision.
Reporting of adverse reactions.
Post-marketing adverse reaction reporting is an important measure. It allows for continuous monitoring of the benefit/risk balance of a medicinal product. Healthcare professionals should report any adverse reactions using the adverse reaction reporting system in Ukraine.
Expiration date
36 months.
Storage conditions
Store in a dry, dark place in the original packaging at a temperature of 15–25 ° C. Keep out of the reach of children.
Packaging
No. 30 (10x3): 10 tablets in a blister; 3 blisters in a cardboard box.
Vacation category
According to the recipe.
Producer
Rivopharm SA.
Location of the manufacturer and address of its place of business
Centro Insema, 6928 Manno, Switzerland.
