Sonapax® 10 mg

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SONAPAX® 10 mg SONAPAX® 25 mg

Composition:

Active substance: thioridazine hydrochloride;

One film-coated tablet contains: thioridazine hydrochloride 10 mg or 25 mg;

Excipients:

film-coated tablets, 10 mg: maize starch, colloidal anhydrous silicon dioxide, sucrose, monohydrate lactose, gelatin, stearic acid, talc, gum arabic (E 414), cochineal red A (E 124);

film-coated tablets, 25 mg: potato starch, sucrose, gelatin, gum arabic (E 414), magnesium stearate, sucrose, talc, quinoline yellow (E 104).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

Tablets Sonapax® 10 mg — round, biconvex, film-coated tablets, light pink in color, uniform in coloration. White in cross-section.

Tablets Sonapax® 25 mg — round, biconvex, film-coated tablets, light yellow in color, uniform in coloration. White in cross-section.

Pharmacotherapeutic group. Antipsychotic agents. Piperidine derivatives of phenothiazine. ATC code N05A C02.

Pharmacological properties.

Pharmacodynamics.

Thioridazine belongs to the group of antipsychotics. It is a piperidine derivative of phenothiazine that significantly affects the nervous system, both central and peripheral. It exerts a predominantly suppressive effect on the brainstem, and to a lesser extent on the cerebral cortex. Peripherally, it produces α-adrenergic blocking, antihistaminic, and pronounced anticholinergic effects, which are more prominent than with other antipsychotics. It does not produce antiemetic effects, causes fewer extrapyramidal disturbances compared to other antipsychotics, and does not suppress intrinsic motor activity.

Thioridazine possesses all typical antipsychotic properties: it exerts weak antipsychotic, anti-manic, and weak antidepressant effects; it does not have activating properties.

Pharmacokinetics.

Thioridazine is rapidly and completely absorbed from the gastrointestinal tract, reaching maximum blood concentration within 2–4 hours. Approximately 95% of the drug is plasma protein-bound. The elimination half-life is 10 hours.

Thioridazine is metabolized in the liver. About 35% is excreted in urine, the remainder in feces (in unchanged form and as metabolites). It crosses the placental barrier and is excreted into breast milk.

Clinical characteristics.

Indications.

Psychological and emotional disorders accompanied by fear, anxiety, and excitement.

In psychiatric practice: acute and subacute schizophrenia, organic psychoses, psychomotor agitation, manic-depressive states, neuroses, alcohol withdrawal syndrome, behavioral disorders in children, agitated states in elderly patients.

Contraindications.

Hypersensitivity to phenothiazine derivatives or to any component of the medicinal product.

Thioridazine is contraindicated in patients with the following conditions: clinically significant heart disorders (heart failure, angina pectoris, cardiomyopathy, or left ventricular dysfunction), QTc interval prolongation syndrome, family history of QTc interval prolongation syndrome. Since thioridazine prolongs the QTc interval, it is contraindicated when used concomitantly with drugs that also have the potential to prolong the QTc interval.

Ventricular arrhythmia, including in medical history, bradycardia, sinoatrial or atrioventricular conduction block of second or third degree, uncorrected hypokalemia or hypomagnesemia. History of cardiac arrhythmia, severe arterial hypotension, pheochromocytoma, porphyria, blood disorders (hypoplastic and aplastic processes), concomitant use with fluoxetine, paroxetine, propranolol, pindolol, fluvoxamine, genetic disorders leading to reduced activity of CYP450 2D6.

Severe photosensitivity, severe depressive states, comatose states of any etiology, dementia, head injuries, progressive systemic diseases of the brain and spinal cord.

Interaction with other medicinal products and other forms of interactions.

When used concomitantly, exhibits a synergistic effect with general anesthetics, opioids, barbiturates, ethanol, and atropine.

When used concomitantly, increases hepatotoxic effects of antidiabetic agents.

When used concomitantly with amphetamine, acts antagonistically.

When used concomitantly with levodopa, reduces its antiparkinsonian effect.

Concomitant use with adrenaline may lead to sudden and significant reduction in blood pressure.

When used concomitantly with guanethidine, reduces its hypotensive effect, but enhances the effect of other antihypertensive agents, increasing the risk of orthostatic hypotension.

Antithyroid agents increase the risk of agranulocytosis.

Quinidine potentiates the cardiodepressant effect of the drug.

Ephedrine promotes abnormal reduction in blood pressure.

Sympathomimetics – increase arrhythmogenic effects.

Reduces the effects of appetite-suppressing agents (except fenfluramine).

Reduces the emetic effect of apomorphine, enhances its inhibitory effect on the central nervous system (CNS).

Increases plasma prolactin concentration and reduces the effectiveness of bromocriptine.

Concomitant use with tricyclic antidepressants, maprotiline, monoamine oxidase inhibitors (MAOIs), and antihistamines may prolong and intensify sedative and anticholinergic effects.

When used concomitantly with thiazide diuretics, hyponatremia may increase;

with lithium preparations – reduced gastrointestinal absorption, accelerated renal excretion of lithium ions, enhanced manifestations of extrapyramidal disorders. Early signs of lithium intoxication (nausea and vomiting) may be masked by the antiemetic effect of thioridazine.

When used concomitantly with beta-blockers, enhances the hypotensive effect.

Pharmacokinetic interactions

Probucol, astemizole, cisapride, disopyramide, erythromycin, pimozide, procainamide, and quinidine promote QT interval prolongation, increasing the risk of ventricular tachycardia.

CYP450 2D6 metabolism

Thioridazine is metabolized by cytochrome CYP450 2D6 and is simultaneously an inhibitor of the enzyme that metabolizes the drug. The plasma concentration and efficacy of thioridazine may be increased and prolonged by drugs that are substrates and/or inhibitors of the CYP450 2D6 isoenzyme, which may lead to severe hypotension, cardiac rhythm disturbances, or CNS-related adverse effects. Examples of drugs that are substrates or inhibitors of cytochrome CYP450 2D6 include antiarrhythmic agents, certain antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and tricyclic compounds, certain neuroleptics, β-blockers, protease inhibitors, opioids, and "ecstasy" (methylenedioxymethamphetamine — MDMA).

Antiepileptic agents

Under the influence of thioridazine, serum phenytoin levels may increase or decrease, thus dose adjustment may be essential. No effect on serum levels of thioridazine or carbamazepine has been established when interacting with carbamazepine.

Barbiturates

The interacting effect of phenothiazines reduces serum levels of both drugs, and also excludes the possibility of increasing serum levels of either drug.

Antihypertensive agents and β-blockers

Like other phenothiazines, thioridazine antagonizes adrenaline and other sympathomimetic agents. Since β-blockers are substrates of cytochrome CYP450 2D6, they may cause bradycardia. Concomitant use of thioridazine with β-blockers is not recommended. In addition, thioridazine may block the action of antihypertensive adrenergic blockers such as guanethidine and clonidine.

Anticoagulants

Concomitant treatment with phenothiazines may increase the effect of anticoagulants. Pharmacodynamic interactions

The effect of thioridazine on the QTc interval may be enhanced when used concomitantly with other drugs that also prolong the QTc interval. Therefore, concomitant use of these drugs with thioridazine is contraindicated. Such drugs include certain antiarrhythmic agents, particularly class IA (e.g., quinidine, disopyramide, and procainamide) and class III (e.g., amiodarone and sotalol), tricyclic antidepressants (e.g., amitriptyline), as well as some tetracyclic antidepressants (such as maprotiline); certain antipsychotics (e.g., phenothiazines and pimozide) and certain antihistamines (e.g., terfenadine), lithium preparations, quinine, pentamidine, and sparfloxacin.

Electrolyte imbalance, particularly hypokalemia, significantly increases the risk of QT interval prolongation. Therefore, concomitant use of drugs causing electrolyte imbalance should be avoided.

CNS depressants

Thioridazine may enhance central nervous system depression caused by other CNS depressants, such as narcotics, alcohol, sedatives, and narcotic analgesics.

MAO inhibitors

Concomitant use may increase sedation, constipation, dry mouth, and hypotension.

Lithium

Serious complications, neurotoxic extrapyramidal side effects, and episodes of sleepwalking have been reported in patients receiving concomitant lithium and phenothiazines, including thioridazine.

Anticholinergic agents

Unwanted anticholinergic effects may result from concomitant use of anticholinergic drugs and thioridazine. Strict monitoring and dose adjustment are required when used concomitantly with agents such as antihistamines, tricyclic antidepressants, and atropine-containing compounds.

Antiparkinsonian agents

The efficacy of both medicinal products may be reduced when used concomitantly with thioridazine.

Adrenergic vasoconstrictors

Due to its ability to reduce blood pressure, phenothiazine may reduce the vasoconstrictor activity of adrenergic vasoconstrictors (e.g., ephedrine, phenylephrine).

Phenylpropanolamine

Ventricular arrhythmias have been reported with concomitant use of phenylpropanolamine and thioridazine.

Thiazide diuretics

Concomitant use of phenothiazine and thiazide diuretics may lead to severe hypotension and diuretic-induced hypokalemia, which may potentiate thioridazine-induced cardiotoxicity.

Antacids, antidiarrheal agents

These agents may reduce gastrointestinal absorption of orally administered phenothiazines. Antacids should not be taken within 2 hours after administration of phenothiazines.

Antidiabetic medicinal products

Phenothiazine affects carbohydrate metabolism and thus interferes with blood glucose control in patients with diabetes mellitus.

Special precautions for use.

QT interval prolongation: Due to the risk of developing arrhythmias caused by QT interval prolongation, thioridazine should be used only after assessment of the risk factor for QT interval prolongation in patients who have undergone ECG and have a normal serum potassium concentration. Thioridazine must not be prescribed to patients with a mean QTc interval of 500 ms. During treatment with Sonapax, serum electrolyte levels should be monitored periodically and any electrolyte abnormalities corrected. Concomitant medications should be carefully evaluated if drugs are used that inhibit CYP 2D6, inhibit thioridazine metabolism via other pathways, or cause QT interval prolongation. The use of thioridazine is contraindicated with such drugs. Caution is advised if the patient is taking medications that may lead to hypokalemia.

Since thioridazine is metabolized by CYP 2D6, patients who are poor metabolizers via this enzyme are also at increased risk of QT interval prolongation. Metabolism may be expected to be slowed in some patients based on experience with other agents metabolized by CYP 2D6. Testing methods to identify poor metabolizers are not widely available. Thioridazine should not be prescribed to patients known to be poor metabolizers.

Anticholinergic properties: Due to the known anticholinergic properties of thioridazine, use with caution in patients with increased intraocular pressure, glaucoma, urinary retention (e.g., prostate hyperplasia), or chronic constipation.

Hepatic disease: Patients with liver disease require regular monitoring of liver function.

Blood dyscrasias: Although rare cases of leukopenia or agranulocytosis have been reported, blood counts should be performed regularly during the first 3–4 months of treatment. If clinical signs of blood dyscrasia appear, a blood count should be performed immediately.

Blood pressure: Orthostatic hypotension is frequently observed in patients taking thioridazine. Blood pressure should be monitored after initiation of thioridazine therapy, especially in elderly patients with orthostatic hypotension or labile circulation.

Alcohol: Since alcohol may increase the risk of hepatotoxic reactions, heat stroke, akathisia, dystonia, or other central nervous system disorders, its consumption should be avoided during thioridazine treatment.

Tolerance: Cases of tolerance to the sedative effect of phenothiazines and cross-tolerance to antipsychotics have been reported. Tolerance may also increase the risk of clinical withdrawal symptoms.

Malignant neuroleptic syndrome.

Malignant neuroleptic syndrome has been observed with the use of neuroleptics. Clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse, changes in blood pressure, tachycardia, diaphoresis, cardiac arrhythmia). Diagnosis of this syndrome is complicated. When establishing this diagnosis, it is important to consider serious conditions such as pneumonia, systemic infections, inadequate treatment of extrapyramidal disorders, anticholinergic toxicity symptoms, myocardial infarction, drug-induced fever, and primary central nervous system pathology. Treatment of malignant neuroleptic syndrome includes immediate discontinuation of neuroleptics, intensive supportive care, and treatment of concomitant conditions. There is no specific treatment. Neuroleptics should be used cautiously if their subsequent use is necessary.

Central nervous system depression.

Like other phenothiazines, thioridazine may potentiate the effects of agents that depress the central nervous system (alcohol, anesthetics, barbiturates, narcotics, opioids, other psychoactive substances), as well as atropine and phosphorus-containing preparations. When high doses of barbiturates are taken concomitantly, severe respiratory depression may develop.

Use caution when prescribing the drug in alcoholism (increased susceptibility to hepatotoxic reactions), breast cancer (phenothiazine-induced prolactin secretion increases the potential risk of disease progression and resistance to endocrine and cytotoxic therapy), hepatic and/or renal insufficiency, active peptic ulcer disease of the stomach or duodenum; in conditions associated with an increased risk of thromboembolic complications, Parkinson’s disease (exacerbation of extrapyramidal effects), epilepsy, myxedema; in chronic conditions associated with impaired respiration (especially in children); Reye’s syndrome (increased risk of hepatotoxicity in children); in cachexia, vomiting (the antiemetic effect of phenothiazines may mask vomiting associated with overdose of other drugs), elderly patients, patients with cardiac arrhythmias, heart disease, myasthenia, epilepsy. In liver disease, regular monitoring of liver function is required. In patients with schizophrenia and a history of seizures, anticonvulsant therapy should be used concurrently with thioridazine. Pigmentary retinopathy, characterized by decreased visual acuity, night vision disturbances, and color vision changes, may occur when thioridazine is used at doses higher than recommended. In such cases, the dose should be reduced. Orthostatic hypotension occurs more frequently in women than in men.

Avoid using epinephrine to treat drug-induced hypotension, as phenothiazines may provoke a paradoxical response. If vasoconstrictors are required, levarterenol or phenylephrine are recommended. Neuroleptics, when used chronically, increase prolactin levels in the blood. Cases of galactorrhea, amenorrhea, gynecomastia, and impotence have been reported. Alcohol consumption should be avoided during treatment, and sun exposure should be limited.

ECG monitoring, including Holter monitoring, should be performed in patients with a history of symptoms that may indicate torsade de pointes (dizziness, palpitations, syncope).

When prescribing neuroleptics, the development of tardive dyskinesia should be minimized as much as possible. During long-term neuroleptic therapy, treatment response should be evaluated, and if necessary, alternative, less toxic agents should be considered; neuroleptics should be used at the lowest effective dose or intermittently.

When diagnosing "malignant neuroleptic syndrome," it is important to consider serious conditions such as pneumonia, systemic infections, inadequate treatment of extrapyramidal disorders, anticholinergic toxicity symptoms, myocardial infarction, drug-induced fever, and primary central nervous system pathology. Treatment of malignant neuroleptic syndrome includes immediate discontinuation of neuroleptics, intensive supportive care, and treatment of concomitant conditions. There is no specific treatment. Neuroleptics should be used cautiously if their subsequent use is necessary.

Sonapax® 10 mg tablets contain cochineal red A (E 124), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

The effect of thioridazine on the fetus is unknown.

The medicinal product should not be used during pregnancy.

Breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

Thioridazine impairs motor coordination and reduces reaction ability, especially at the beginning of treatment. Patients should not drive or operate machinery during therapy.

Dosage and Administration

The dosage should be individually determined by a physician; the lowest effective therapeutic dose must be established for each patient separately. The daily dose should be divided into 2–4 administrations.

Adults and adolescents

Psychiatric and emotional disorders such as schizophrenia, manic psychoses, and similar conditions: 150–600 mg daily. The initial dose may be increased to 200 mg in patients with acute schizophrenia. The daily dose may be increased up to 800 mg in resistant patients under medical supervision, but not for longer than 4 weeks.

Treatment of psychosis in outpatient settings: daily dose of 50–300 mg; in patients with depression and elderly patients: 25–200 mg; alcohol withdrawal syndrome: 100–200 mg; severe non-psychotic mental disorders: 25–150 mg. As a sedative and tranquilizer, Sonapax® should be administered to adults in a daily dose of 10–75 mg.

Usual pediatric dosing

Children aged 5–12 years: 0.25–3 mg per kg of body weight daily, divided into 2–4 doses. Severe disorders: 25 mg 2–3 times daily. Maximum daily dose: 300 mg. When the required dose is not a multiple of 25 mg, thioridazine in appropriate dosage forms and strengths should be used.

Children

Do not use in children under 5 years of age.

Overdose

Symptoms of overdose, including symptoms typical of phenothiazine overdose:

Cardiovascular system: cardiac arrhythmia, arterial hypotension, shock, ECG changes, QT and PR interval prolongation, ST and T wave changes, bradycardia, sinus tachycardia, atrioventricular block, ventricular tachycardia, ventricular fibrillation, torsade de pointes-type rhythm disturbances, myocardial changes;

Nervous system: mydriasis, miosis, dry skin, dry mouth, nasal mucosa hyperemia, nasal congestion, urinary retention, visual disturbances, speech impairment, drowsiness, disturbances of consciousness and orientation, visual acuity, excitement, motor hyperactivity, extrapyramidal symptoms, seizures, coma, agitation, hypothermia, hyperthermia, insomnia, areflexia;

Respiratory system: respiratory depression, apnea, pulmonary edema;

Gastrointestinal tract: decreased peristalsis, constipation, ileus, paralytic intestinal obstruction, nausea, vomiting;

Urinary system: oliguria, uremia. The toxic dose and blood concentration of phenothiazines have not been precisely established.

Treatment: gastric lavage with activated charcoal. Ensure airway patency and perform cardiovascular and ECG monitoring to detect arrhythmias. Correct electrolyte and acid-base imbalances. Use lidocaine, phenytoin, isoproterenol, and defibrillation as needed. Avoid the use of disopyramide, procainamide, and quinidine, as they, like thioridazine, prolong the QT interval (see sections "Special precautions" and "Contraindications"). Exercise caution when using lidocaine, as it increases the risk of seizures.

For treatment of arterial hypotension, administer intravenous fluids and vasoconstrictor agents (for refractory hypotension, use phenylephrine, norepinephrine, or metaraminol, as well as epinephrine and dopamine).

Treatment should aim to reduce drug absorption and enhance elimination.

Do not induce vomiting due to the risk of dystonia and aspiration of vomitus.

For treatment of acute extrapyramidal symptoms, use diphenhydramine hydrochloride or benztropine mesylate.

For treatment of seizures, avoid the use of barbiturates, as they may exacerbate phenothiazine-induced respiratory depression.

Forced diuresis, hemoperfusion, and hemodialysis are ineffective due to the high degree of protein binding of the drug.

Adverse reactions.

Central nervous system and sensory organs: drowsiness, sluggishness, especially when taking high doses at the beginning of treatment, which usually disappears during continued therapy or upon dose reduction; pseudoparkinsonism with other extrapyramidal symptoms, confusion, hyperactivity, lethargy, psychotic reactions, emotional lability, headache, insomnia, emotional disturbances, impaired thermoregulation, lowered seizure threshold, loss of consciousness, blurred vision, nasal congestion, pallor, miosis, yawning, emotional excitement, visual disturbances.

Endocrine system: galactorrhea, breast enlargement, edema.

Cardiovascular system: arterial hypotension, tachycardia, palpitations, QT interval prolongation, which may lead to the development of arrhythmias such as torsade de pointes, polymorphic ventricular tachycardia, and sudden death (see "Special precautions"), other ECG changes (prolongation of the QT interval, depression or inversion of the T wave, bifurcation of the T or U wave). These changes are reversible, occur due to altered repolarization, and are not associated with myocardial damage. QT interval prolongation is associated with severe ventricular arrhythmias and sudden death; arterial hypotension has been reported as a result of cardiac attack.

Gastrointestinal tract: xerostomia, increased appetite, dyspepsia, weight gain, hypertrophy of lingual papillae, dry mouth, nausea, vomiting, diarrhea, constipation, anorexia, paralytic ileus.

Skin: skin rashes, erythema, urticaria, exfoliative dermatitis, contact dermatitis, skin melanosis (with prolonged use at high doses), photosensitivity reactions.

Blood system: agranulocytosis, leukopenia, eosinophilia, thrombocytopenia, anemia, aplastic anemia, pancytopenia, granulocytopenia.

Allergic reactions: fever, laryngeal edema, angioneurotic edema, bronchospastic syndrome, nasal congestion, asthma, allergic skin reactions.

Hepatobiliary system: cholestatic jaundice, bile stasis.

Psychiatric disorders: akathisia, agitation, motor restlessness, dystonic reactions, trismus, torticollis, opisthotonus, oculogyric crisis, tremor, muscle rigidity, akinesia.

Tardive dyskinesia: prolonged use of antipsychotic agents may lead to the development of this type of dyskinesia. This syndrome is characterized by involuntary choreic movements, including movements of the tongue, face, mouth, lips, and jaw (protrusion of the tongue, puffing of cheeks, puckering of the mouth, chewing movements), facial grimacing, limb movements. The severity of the syndrome and the degree of impairment vary. The syndrome may occur during treatment, upon dose adjustment, or after discontinuation of treatment. Early diagnosis of this symptom is essential. Movements may diminish or even disappear if antipsychotic medications are discontinued. Reversibility of these reactions is more pronounced with short-term treatment than with prolonged use. It is important to diagnose this symptom promptly. Patients should be monitored, and if possible, the dose of antipsychotics should be reduced. It should be noted that antipsychotic medications may mask the symptoms of this syndrome.

Neuroleptic malignant syndrome: prolonged use of antipsychotic drugs is associated with the development of neuroleptic malignant syndrome, whose clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status, disturbances of consciousness, autonomic dysfunction (arrhythmic pulse, changes in blood pressure, tachycardia, diaphoresis, cardiac arrhythmia).

Reproductive system: menstrual cycle disturbances, changes in libido, gynecomastia, lactation, weight gain, edema, false-positive pregnancy tests.

Urinary and genital system: urinary retention, urinary incontinence, decreased libido, ejaculation disorders, dysmenorrhea, hyperprolactinemia, gynecomastia, paradoxical ischuria, dysuria, priapism.

Other: hyperpyrexia, rare episodes of salivary gland swelling, priapism. Paradoxical reactions and behavioral disorders have been reported, including excitement, exacerbation of psychosis, disturbances of consciousness due to toxic effects, progressive pigmentation of the skin or conjunctiva with or without color change of the sclera and cornea, opacity of the anterior surface of the eye lens, systemic lupus erythematosus.

The occurrence of adverse reactions observed with phenothiazine derivatives cannot be excluded. The most common neurological disorders are parkinsonism and akathisia, as well as an increased risk of agranulocytosis and leukopenia in elderly patients.

Shelf life. 4 years.

Storage conditions. Store in a dry place at a temperature not exceeding 25 °C.

Packaging.

For 10 mg coated tablets: 30 tablets in a blister; 2 blisters together with the instruction for medical use are packed in a cardboard box;

for 25 mg coated tablets: 20 tablets in a blister; 3 blisters together with the instruction for medical use are packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Elfa Pharmaceutical Works A.T.

Manufacturer's address and place of business.

58-500 Jelenia Góra, ul. Wincentego Pola 21, Poland.