Tiaprozan

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TIAPROSAN® (TIAPROSAN®)

Composition:

Active substance: tiapride;

1 tablet contains tiapride hydrochloride corresponding to tiapride 100 mg;

Excipients: mannite (E 421), microcrystalline cellulose, povidone, sodium starch glycolate (type A), magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties:

white or almost white, round tablets with a crosswise score line on one side, approximately 9.5 mm in diameter.

Pharmacotherapeutic group. Antipsychotic agents.

ATC code N05A L03.

Pharmacological Properties

Pharmacodynamics

Tiapride is an atypical neuroleptic, independent of adenylate cyclase, which selectively blocks dopaminergic D2 receptors. Its affinity for dopaminergic D1 receptors is low. It has been demonstrated that its activity potentiates receptor stimulation and sensitization.

The anxiolytic effect of tiapride has been demonstrated in several animal stress models, including experiments aimed at studying signs of withdrawal. In addition, tiapride has been shown to exert a positive analgesic effect and promote mental clarity in elderly patients. The mechanism of its anxiolytic action is still unknown, although it is known to be distinct from its antidopaminergic activity.

Pharmacokinetics

Absorption

After oral administration of 200 mg of tiapride, maximum plasma concentration of 1.3 µg/mL is reached within 1 hour.

The bioavailability of tiapride in tablet form is 75%. Bioavailability increases by 20% when tiapride is taken before meals. In elderly individuals, absorption of the drug is slowed.

Distribution in the body

Distribution in the body is rapid (less than 1 hour). Tiapride penetrates the blood-brain and placental barriers without accumulation. Animal experiments have shown that passage into breast milk occurs at a milk/blood ratio of 1:2. Tiapride does not bind to plasma proteins, but binds slightly to erythrocytes.

Metabolism
In humans, tiapride is minimally metabolized. 70% of the administered dose is excreted unchanged in urine.

Elimination from the body

The elimination half-life of the drug is 2.9 hours in women and 3.6 hours in men. Elimination occurs primarily via urine; renal clearance is 330 mL/min and correlates with creatinine clearance.

Preclinical safety data

Acute and subchronic toxicity of tiapride have been shown to be low; signs of intoxication are generally due to central antidopaminergic effects and hormonal changes in the body (hyperprolactinemia). No cases of mutagenicity have been recorded. Embryo-fetal development studies in animals did not demonstrate any direct or indirect teratogenic effects or embryo-fetal toxicity of tiapride in rodents. However, studies in rabbits showed some embryotoxic effects at elevated test doses (80 and 160 mg/kg/day). Data from neurobehavioral studies in offspring of animals are still insufficient. In peri- and postnatal studies in rats, toxic effects on offspring were observed when high doses of the drug were administered. With prolonged administration of the drug in experimental animals, changes in genital organs (testes, prostate, uterus, ovaries) occurred, fertility was impaired. Increased hyperplasia and neoplasia of mammary glands, pituitary gland, and endocrine pancreatic and adrenal tissues were observed. All the above-described effects occurred as a result of chronically elevated prolactin levels in blood.

Clinical characteristics.

Indications.

Adults:

• Short-term treatment of agitation and aggressive states in patients with alcohol dependence;
• Treatment of severe forms of chorea in Huntington's disease;
• Treatment of severe forms of tic disorders when non-pharmacological treatments are insufficient.

Patients aged 6 years and adolescents:

• Treatment of severe forms of tic disorders when non-pharmacological treatments are insufficient.

Elderly patients:

• Short-term treatment of agitation and aggressive states in elderly patients.

Contraindications.

• Hypersensitivity to the active substance or to any component of the medicinal product.
  • Prolactin-dependent tumours (e.g., pituitary prolactinoma).
• Breast cancer.
• Phaeochromocytoma.
• Combination with levodopa or other dopaminergic agonists (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations

Concomitant use with dopaminergic agonists should be avoided, except in patients with Parkinson's disease (cabergoline, quinagolide), due to a reciprocal antagonism between dopaminergic agonists and neuroleptics, resulting in mutual reduction of their effects.

Not recommended combinations

Due to the risk of neuroleptic malignant syndrome (NMS), tiapride should be administered with caution in patients who are simultaneously taking other neuroleptics or medicinal products that may cause NMS (see "Special warnings and precautions for use"). Combination with the following medicinal products that may cause torsades de pointes or QT interval prolongation:

• Class Ia antiarrhythmics, such as quinidine, hydroquinidine, disopyramide.
  • Class III antiarrhythmics, such as amiodarone, sotalol, dofetilide, ibutilide.
  • Some neuroleptics, such as sulpiride, pipothiazide, sertindole, veralipride, chlorpromazine, levomepromazine, trifluoperazine, thiamemazine, sulpiride, pimozide, haloperidol, droperidol, fluphenazine, pipamperone, flupentixol, cyamemazine, cyproheptadine.
• Some antiparasitic agents, such as halofantrine, lumefantrine, pentamidine.
• Other medicinal products such as bepridil, cizapride, intravenous erythromycin, intravenous vincamine, intravenous spiramycin, moxifloxacin, difemethil, mizolastine.
• Due to the increased risk of ventricular arrhythmias, particularly ventricular fibrillation, if possible, antibacterial therapy that may induce ventricular fibrillation should be discontinued. If combined therapy cannot be stopped, QT interval should be checked on ECG before starting treatment.

Alcohol

Alcohol enhances the sedative effect of neuroleptics; therefore, consumption of alcoholic beverages and use of medicinal products containing ethanol should be avoided during treatment. Impairment of attention may be particularly dangerous when driving or operating machinery.

Alcohol consumption may cause electrolyte imbalance and thereby prolong the QT interval (see "Special warnings and precautions for use").

Levodopa

Mutual antagonism between levodopa and neuroleptics occurs. In patients with Parkinson's disease, the minimum effective doses of both drugs should be used.

Dopaminergic agonists, other than levodopa (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, ropinirole, selegiline)

In patients with Parkinson's disease, due to the mutual antagonism between dopaminergic agonists and neuroleptics, dopaminergic agents may induce or exacerbate psychotic disorders. When neuroleptic therapy cannot be avoided in patients with Parkinson's disease who are receiving dopaminergic agonists, the use of these medicinal products should be tapered and discontinued (abrupt withdrawal of dopaminergic agonists may trigger NMS).

Methadone

Increased risk of ventricular arrhythmia, particularly of the torsades de pointes type.

Combinations requiring special caution

• Medicinal products that cause bradycardia (particularly class Ia antiarrhythmics, beta-blockers, certain class II antiarrhythmics, certain calcium channel blockers, cardiac glycosides, pilocarpine, cholinesterase inhibitors).

Increased risk of ventricular arrhythmia, particularly torsades de pointes. Clinical monitoring and ECG are required.

• Beta-blockers in cardiac failure (bisoprolol, carvedilol, metoprolol, nebivolol). Increased risk of ventricular arrhythmias, particularly torsades de pointes. Clinical monitoring and ECG are required.
• Medicinal products that reduce potassium levels (potassium-depleting diuretics, stimulant laxatives, intravenous amphotericin B, glucocorticoids, tetracosactide).

Increased risk of ventricular arrhythmia, particularly torsades de pointes. Potassium levels should be corrected before initiating treatment, followed by clinical monitoring and ECG.

• Antihypertensive agents (all).

Enhanced antihypertensive effect, increased risk of orthostatic hypotension.

• Other agents that depress CNS function: morphine derivatives (opioid analgesics, antitussives, and opioid substitution therapy), barbiturates, benzodiazepines, other non-benzodiazepine anxiolytics, hypnotics, neuroleptics, antidepressants with sedative properties (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1 antihistamines, centrally acting antihypertensives, other medicinal products (baclofen, thalidomide, pizotifen).

Increased central sedation. Impairment of attention may be particularly dangerous when driving or operating machinery.

• Beta-blockers (except esmolol, sotalol, and beta-blockers used in cardiac failure). Vasodilatory effect and risk of hypotension, particularly postural (additive effect).
• Nitrate derivatives and related substances.

Special precautions for use.

Malignant neuroleptic syndrome

When using other drugs with neuroleptic activity concomitantly with tiapride, there is a risk of developing neuroleptic malignant syndrome (NMS), which may lead to potentially fatal complications characterized by hyperthermia, muscle rigidity, and autonomic dysfunction (see section "Adverse reactions"). Cases have also been reported with atypical features such as hyperthermia even in the absence of muscle rigidity or hypertension and subfebrile conditions. In case of suspected NMS or the appearance of unexplained hyperthermia, which may be considered an early symptom of typical or atypical NMS, the tiapride treatment course should be discontinued under medical supervision.

Due to the risk of NMS development associated with the use of any neuroleptic agent, tiapride should be administered with caution to patients who are concurrently taking other neuroleptics or drugs known to induce NMS (see section "Interaction with other medicinal products and other forms of interaction").

Neuroleptic drugs may lower the seizure threshold in epileptic seizures. Although this effect has not been confirmed with tiapride, careful monitoring is required in patients with a history of epilepsy during tiapride treatment.

The dose of the drug should be reduced in patients with renal impairment due to the potential risk of coma resulting from overdose (see sections "Dosage and administration" and "Overdose").

Tiapride should be prescribed to patients with Parkinson's disease only in exceptional cases.

Elderly patients should be treated with tiapride, as with other neuroleptic drugs, with caution due to the potential risk of consciousness depression up to coma.

Breast cancer

Tiapride may cause an increase in prolactin levels; therefore, caution should be exercised when administering it to patients with a personal or family history of breast cancer.

QT interval prolongation

Tiapride may cause QT interval prolongation. This effect increases the risk of serious ventricular arrhythmias such as torsades de pointes (see section "Adverse reactions"). Prior to any administration, if clinically feasible, it is recommended to monitor factors that may contribute to this rhythm disorder, such as:

• heart rate less than 55 beats per minute (bradycardia);
• electrolyte imbalance, particularly hypokalemia;
• congenital QT interval prolongation, positive family history of QT interval prolongation;
• concomitant use of drugs that may cause severe bradycardia (<55 beats per minute), electrolyte imbalance, conduction disturbances, or QT interval prolongation (see section "Interaction with other medicinal products and other forms of interaction");
• alcohol consumption, which may cause electrolyte imbalance and thereby prolong the QT interval (see section "Interaction with other medicinal products and other forms of interaction").

Tiapride should be prescribed with particular caution to patients with risk factors that may lead to QT interval prolongation.

When prescribing tiapride, continuous cardiac monitoring should be performed whenever possible.

Ischemic stroke of the brain

In randomized, placebo-controlled clinical trials involving elderly patients with dementia, treatment with certain atypical antipsychotics was associated with a threefold increase in the risk of stroke. The mechanism of this increased stroke risk is unknown. An increased risk of stroke with other antipsychotics or in other patient populations cannot be excluded. When prescribing tiapride to patients at increased risk of stroke, a careful benefit-risk assessment is required.

Increased mortality in elderly patients with dementia

In elderly patients with dementia treated with antipsychotic drugs, an increased number of deaths has been observed. An analysis of 17 placebo-controlled clinical trials (with a mean study duration of 10 weeks), primarily involving patients treated with atypical antipsychotics, showed a 1.6–1.7-fold increase in mortality among patients receiving antipsychotics compared to the placebo control group. During a typical 10-week clinical trial, the mortality rate in patients receiving antipsychotics was approximately 4.5%, compared to 2.6% in the control group. Although various causes of death were reported in the antipsychotic-treated group, most deaths were associated with cardiovascular (e.g., cardiac collapse, sudden death) or infectious (e.g., pneumonia) conditions. Observational studies suggest that, similar to atypical antipsychotics, the risk of mortality may also be increased with conventional antipsychotics. However, available data do not allow precise quantification of the risk associated with antipsychotic use.

Venous thromboembolism (VTE)

An increased incidence of VTE has been reported with the use of neuroleptics. Since patients treated with neuroleptics often have acquired risk factors for VTE, these factors should be identified before and during treatment, and appropriate preventive measures should be implemented.

Children

Tiapride has not been thoroughly studied in children; therefore, caution should be exercised when prescribing it to pediatric patients (see section "Dosage and administration").

Duration of treatment

The efficacy and safety of tiapride in the treatment of Huntington's chorea have been systematically evaluated for no longer than 3 weeks.

The efficacy and safety of tiapride in the treatment of tic disorders (including Gilles de la Tourette syndrome) have been systematically evaluated for no longer than 10 weeks.

When tiapride is used for longer periods, the physician should periodically reassess the long-term benefit for each individual patient.

Cases of leukopenia, thrombocytopenia, and agranulocytosis have been reported with the use of antipsychotic drugs, including tiapride. Unexplained infections or fever may be manifestations of hematological disorders and require immediate hematological evaluation (see section "Adverse reactions").

Tiaprosan® contains less than 1 mmol (23 mg) of sodium per tablet; therefore, it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

Experience with the use of tiapride during pregnancy is insufficient or lacking. Tiapride crosses the placenta. Animal studies have shown that the drug has reproductive toxicity.

The medicinal product is not recommended during pregnancy and in women of childbearing potential who are not using reliable contraception. Newborns exposed to antipsychotic drugs (including Tiaprosan®) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal disorders and/or withdrawal symptoms. These symptoms may vary in duration and severity (see section "Adverse reactions").

Reports have described agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress, or feeding disorders in newborns. Therefore, newborns should be closely monitored.

Breastfeeding period

Animal studies have shown that tiapride passes into breast milk. It is unknown whether tiapride passes into human breast milk. A risk to breastfed infants cannot be excluded. Therefore, when using the drug, a decision must be made regarding the benefit of treatment for the mother versus the risk to the infant (either discontinuing breastfeeding or discontinuing treatment with Tiaprosan®).

Fertility

In animals, decreased fertility associated with the pharmacological action of the drug (via prolactin) has been observed. Tiapride may similarly affect human fertility (see section "Adverse reactions").

Ability to influence reaction speed when driving or operating machinery

Tiapride may cause sedation and thus impair the ability to drive or operate machinery.

Method of Administration and Dosage

The physician should always select the lowest effective dose of tiapride for each patient. Considering the patient's condition, therapy should be initiated with low doses of tiapride, gradually increasing the dose. The daily dose should be divided into 2–4 doses, unless otherwise prescribed.

Tablets may be taken during meals or at any other time.

The medicinal product is intended for treatment of adults, adolescents, and children aged 6 years and older.

Adults

Short-term management of agitation and aggressive states in patients with alcohol dependence:

Usual dose: 200 mg, maximum 300 mg per day. The duration of treatment should not exceed 28 days.

Severe chorea in Huntington’s disease:

Usual dose: 300–800 mg per day. Treatment should be initiated with a low dose – 25 mg per day, then gradually increased until the minimum effective dose is reached. In some patients, the dose may exceed 1200 mg per day.

Severe tic disorders when non-pharmacological treatment is insufficient:

Usual dose: 300–800 mg per day.

Treatment should be initiated with a low dose – 25 mg per day, then gradually increased until the minimum effective dose is achieved.

Children aged 6 years and adolescents

Usual dose: 100–150 mg per day. Maximum daily dose: 300 mg.

It is recommended to prescribe the drug in another pharmaceutical form for children.

Elderly patients

Initial dose: 100 mg/day. If necessary, the dose may be gradually increased up to a maximum of 300 mg/day.

Special patient groups

Severe renal impairment

In patients with endogenous creatinine clearance in the range of 30–60 ml/min, the dose should be reduced by 75% of the normal dose; in patients with endogenous creatinine clearance in the range of 10–30 ml/min, the dose should be reduced by 50% of the normal dose; in patients with endogenous creatinine clearance less than 10 ml/min, the dose should be reduced by 25% of the normal dose.

Severe hepatic impairment

The metabolism of the drug is not extensive; therefore, dose reduction is not usually necessary in this case.

Children

As experience with the use of tiapride in children is limited, caution should be exercised when administering the drug to this patient group.

Overdose

Symptoms. Experience with tiapride overdose is limited. Symptoms may include somnolence and sedation, coma, arterial hypotension, and extrapyramidal symptoms.

In cases of acute overdose, the possibility of concomitant intake of other medicinal products should be considered.

Fatal cases have been reported primarily when the drug was used in combination with other psychotropic substances.

Treatment. Since tiapride is very poorly dialyzed, hemodialysis is ineffective for removing the substance. No specific antidote is known. Therefore, symptomatic intensive therapy is required, along with careful continuous monitoring of cardiac function (risk of QT interval prolongation with subsequent ventricular arrhythmia) until complete resolution of overdose symptoms, as well as close monitoring of respiratory function.

In cases of severe extrapyramidal symptoms, anticholinergic agents should be administered.

Adverse Reactions

Adverse reactions observed during administration of tiapride hydrochloride are systematized by organ systems and frequency of occurrence:

Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), including isolated cases; frequency not known (cannot be estimated from available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

It should be noted that in some cases, adverse reactions may be difficult to distinguish from symptoms of the underlying disease.

Blood and lymphatic system disorders

Rare: Leukopenia, neutropenia, and agranulocytosis (see "Special precautions for use").

Endocrine system disorders

Common: Hyperprolactinemia, which may lead to amenorrhea, abnormal orgasm, breast enlargement, breast pain, galactorrhea, gynecomastia, erectile dysfunction; these effects usually resolve after discontinuation of the drug.

Metabolism and nutrition disorders

Rare: Hyponatremia, Parhon syndrome (syndrome of inappropriate antidiuretic hormone secretion – SIADH).

Psychiatric disorders

Common: Insomnia, agitation, apathy.

Uncommon: Confusion, hallucinations.

Nervous system disorders

Common: Somnolence, dizziness, vertigo, headache; parkinsonism and parkinsonism-like symptoms such as tremor, hypertonia, hypokinesia, and increased salivation. Most symptoms are reversible with administration of anti-parkinsonian agents.

Uncommon: Akathisia, dystonia (e.g., spasms, torticollis, oculogyric crisis, trismus). Most symptoms are reversible with anti-parkinsonian agents. Convulsions, syncope.

Rare: Acute dyskinesia. Most symptoms are reversible with anti-parkinsonian agents. As with all other antipsychotics, tardive dyskinesia (characterized by rhythmic involuntary movements, especially of the tongue and/or face) may develop after treatment with tiapride lasting more than three months. In such cases, anti-parkinsonian agents are ineffective and may even worsen symptoms.

Neuroleptic Malignant Syndrome (NMS) – a potentially life-threatening complication associated with antipsychotic therapy, which may be fatal.

Loss of consciousness.

Cardiac disorders

Rare: QT interval prolongation, ventricular arrhythmia manifesting as torsades de pointes; ventricular tachycardia, which may lead to ventricular fibrillation or cardiac arrest and sudden death.

Vascular disorders

Uncommon: Hypotension, usually orthostatic, deep vein thrombosis.

Rare: Pulmonary embolism, sometimes fatal (see "Special precautions for use").

Respiratory, thoracic and mediastinal disorders

Rare: Aspiration pneumonia, respiratory failure associated with concomitant use of other CNS depressants.

Gastrointestinal disorders

Uncommon: Constipation.

Rare: Intestinal obstruction, bowel obstruction.

Hepatobiliary disorders

Rare: Increased levels of liver enzymes.

Skin and subcutaneous tissue disorders

Uncommon: Rash, including erythematous and maculopapular.

Rare: Urticaria.

Musculoskeletal and connective tissue disorders

Rare: Elevated creatine phosphokinase in blood, rhabdomyolysis.

Conditions related to pregnancy, puerperium and perinatal period

Frequency not known: Withdrawal syndrome in newborns (see section "Pregnancy and breastfeeding").

Reproductive system and breast disorders

Uncommon: Amenorrhea, abnormal orgasm.

Rare: Breast enlargement, breast tenderness, galactorrhea, gynecomastia, erectile dysfunction.

General disorders and administration site conditions

Common: Weakness, asthenia.

Uncommon: Weight gain.

Injury, poisoning and procedural complications

Frequency not known: Falls (particularly in elderly patients).

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Store in the original packaging, protected from light, in a place inaccessible to children, at a temperature not exceeding 25 °C.

Packaging.

10 tablets in a blister pack; 3, 6, or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

PRO.MED.CS Prague a.s.

Manufacturer's address.

Telčská 377/1, Michle, Prague 4, 140 00, Czech Republic.