Betamax

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT BETA MAX (BETAMAX)

Composition:

Active ingredient: sulpiride;

One tablet contains 50 mg or 100 mg of sulpiride;

Excipients: lactose monohydrate; methylcellulose; potato starch; dried potato starch; colloidal anhydrous silicon dioxide; magnesium stearate; talc.

Medicinal form. Tablets.

Main physicochemical properties:

50 mg tablets – round, flat-cylindrical tablets of white or almost white color with a bevel edge;

Tablet dimensions:

diameter: 6.0 ± 0.2 mm, height: 2.1 ± 0.3 mm;

100 mg tablets – round, flat-cylindrical tablets of white or almost white color with a bevel edge;

Tablet dimensions:

diameter: 7.0 ± 0.2 mm, height: 3.1 ± 0.3 mm.

Pharmacotherapeutic group.

Antipsychotic agents. ATC code: N05A L01.

Pharmacological properties.

Pharmacodynamics.

Sulpiride affects dopaminergic neurotransmission in the brain as a dopamine agonist, thereby exerting an activating effect. At higher doses, sulpiride also reduces productive symptomatology.

Pharmacokinetics.

Absorption

After oral administration of a single 50 mg tablet, the maximum plasma concentration of sulpiride (0.25 mg/L) is reached within 3–6 hours.

Distribution

The bioavailability of oral dosage forms is 25–35%, with wide individual variations; sulpiride exhibits a linear pharmacokinetic profile following administration in doses ranging from 50 mg to 300 mg.

Sulpiride rapidly distributes into body tissues: the apparent volume of distribution at steady state is 0.94 L/kg. Plasma protein binding is 40%.

Sulpiride is detected in breast milk in small amounts and may cross the placental barrier.

Biotransformation

Sulpiride is practically not metabolized in the human body.

Elimination

Sulpiride is primarily excreted from the body via the kidneys by glomerular filtration. Renal clearance is 126 mL/min. The elimination half-life from plasma is 7 hours.

Clinical characteristics.

Indications.

• Short-term symptomatic treatment of anxiety disorders in adults when conventional therapeutic measures have not been effective.
• Severe behavioural disorders (agitation, self-injury, stereotypy) in children aged 6 years and older, particularly in patients with autistic syndromes.

Contraindications.

• Hypersensitivity to sulpiride or to any of the excipients of the medicinal product.
• Prolactin-dependent tumours (e.g., prolactin-secreting pituitary adenoma (prolactinoma) and breast cancer).
• Known or suspected diagnosis of phaeochromocytoma.
• Acute porphyria.
• Combination with dopamine receptor agonists not indicated for the treatment of Parkinson’s disease (cabergoline, quinagolide), citalopram, escitalopram, hydroxyzine, domperidone, and piperazine (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Sedatives

It should be considered that many medicinal products may exert additive inhibitory effects on the central nervous system (CNS), leading to reduced mental alertness. These medicinal products include morphine derivatives (analgesics, antitussives, and substitution therapy), neuroleptics, barbiturates, benzodiazepines, non-benzodiazepine anxiolytics (such as meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedative H1-antihistamines, antihypertensives with central action, baclofen, and thalidomide.

Medicinal products that may induce paroxysmal ventricular tachycardia (torsades de pointes)

This serious cardiac arrhythmia may be caused by several medicinal products, with or without antiarrhythmic activity. Precipitating factors include hypokalaemia (see "Potassium-sparing agents") and bradycardia (see "Agents causing bradycardia"), or the presence of congenital or acquired QT interval prolongation.

Such medicinal products include, in particular, antiarrhythmic agents of class Ia and III, and some neuroleptics. This effect is also induced by other agents not belonging to these classes.

Dolasetron, erythromycin, spiramycin, and vinca alkaloids only in intravenous formulations may interact in this way.

Concomitant administration of two "torsadogenic" (inducing torsades de pointes) agents is generally contraindicated.

However, some of these agents are exceptions, as their use cannot be avoided. Therefore, they are not recommended for use in combination with medicinal products that may induce torsades de pointes. This applies to methadone, antiparasitic agents (chloroquine, halofantrine, lumefantrine, pentamidine), and neuroleptics.

However, citalopram, domperidone, and escitalopram are not included among these exceptions: their concomitant use with all medicinal products that may induce torsades de pointes is contraindicated.

Contraindicated combinations (see section "Contraindications").

Citalopram, escitalopram

Increased risk of ventricular arrhythmias, particularly paroxysmal torsade de pointes (torsades de pointes).

Agonists of dopamine receptors not indicated for the treatment of Parkinson’s disease (cabergoline, quinagolide)

Mutual antagonism exists between dopamine agonists and neuroleptics.

Domperidone

Increased risk of ventricular arrhythmia, particularly paroxysmal torsade de pointes (torsades de pointes).

Hydroxyzine

Increased risk of ventricular arrhythmia, particularly paroxysmal torsade de pointes (torsades de pointes).

Piperaquine

Increased risk of ventricular arrhythmia, particularly paroxysmal torsade de pointes (torsades de pointes).

Unwanted combinations (see section "Special precautions for use").

Antiparasitic agents that may induce paroxysmal ventricular tachycardia (torsades de pointes) (chloroquine, halofantrine, lumefantrine, pentamidine)

Increased risk of ventricular arrhythmias, particularly paroxysmal torsade de pointes (torsades de pointes). If possible, one of the two agents should be discontinued.

If concomitant use cannot be avoided, QT interval should be checked before initiation and ECG monitoring should be performed during treatment.

With anti-Parkinsonian dopamine agonists (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, ropinirole, rasagiline, rotigotine, selegiline)

Mutual antagonism exists between dopamine agonists and neuroleptics.

Dopamine agonists may induce or exacerbate psychiatric disorders. In patients with Parkinson’s disease receiving dopamine agonist therapy who require neuroleptic treatment, the dose of dopamine agonists should be gradually reduced (sudden withdrawal may place the patient at risk of neuroleptic malignant syndrome).

Other agents that may induce torsade de pointes (torsades de pointes) (class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, dronedarone, sotalol, dofetilide, ibutilide) and other agents such as arsenic compounds, diphenylhydantoin, intravenous dolasetron, domperidone, intravenous erythromycin, hydroxychloroquine, levofloxacin, mequitazine, mizolastine, prucalopride, intravenous vinca alkaloids, moxifloxacin, intravenous spiramycin, toremifene, and vandetanib)

High risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes).

Other neuroleptics that may induce torsade de pointes (torsades de pointes) (amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, flufenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazide, sulpiride, tiapride, zuclopenthixol)

High risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes).

Alcohol (beverage or excipient)

Potentiation of sedative effects of neuroleptics.

Due to impaired concentration ability, driving vehicles and operating machinery may be hazardous. Patients should avoid consuming alcoholic beverages or using medicinal products containing alcohol.

Levodopa

Mutual antagonism exists between levodopa and neuroleptics.

In patients with Parkinson’s disease receiving dopamine agonist and neuroleptic therapy, the minimum effective doses of both agents should be prescribed.

With methadone

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes).

Combinations requiring caution

Anagrelide

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes). ECG monitoring and clinical surveillance are required during concomitant use.

Azithromycin

Increased risk of ventricular arrhythmias, particularly polymorphic ventricular tachycardia. ECG monitoring and clinical surveillance are required during concomitant use.

Beta-blockers used in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol)

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes). Clinical monitoring and ECG control are required.

Agents causing bradycardia (e.g., class Ia antiarrhythmics, beta-blockers, some class III antiarrhythmics, some calcium channel blockers, crizotinib, digoxin glycosides, pasireotide, pilocarpine, cholinesterase inhibitors)

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes). Clinical monitoring and ECG control are required.

Cyprofloxacin, levofloxacin, norfloxacin

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes). ECG monitoring and clinical surveillance are required during concomitant use.

Clarithromycin

Increased risk of ventricular arrhythmias, particularly polymorphic ventricular tachycardia. ECG monitoring and clinical surveillance are required during concomitant use.

Potassium-sparing agents (potassium-sparing diuretics, alone or in combination, stimulant laxatives, glucocorticoids, tetracosactide, and intravenous amphotericin B)

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes).

Existing hypokalaemia should be corrected before administration. Clinical monitoring, electrolyte control, and ECG monitoring are required.

Lithium

Risk of neuropsychiatric changes suggestive of neuroleptic malignant syndrome or lithium toxicity. Regular clinical monitoring and laboratory tests are indicated, especially at the beginning of concomitant therapy.

If early signs of neurotoxicity appear, discontinuation of one of the two agents is recommended.

Ondansetron

Increased risk of ventricular arrhythmias, particularly torsade de pointes (torsades de pointes). ECG monitoring and clinical surveillance are required during concomitant use.

Roxithromycin

Increased risk of ventricular arrhythmias, particularly polymorphic ventricular tachycardia. ECG monitoring and clinical surveillance are required during concomitant use.

Sucralfate

Reduced gastrointestinal (GI) absorption of sulpiride.

A time interval (more than 2 hours, if possible) should be maintained between administration of sucralfate and sulpiride.

With locally acting gastrointestinal agents, antacids, and activated charcoal

Reduced gastrointestinal (GI) absorption of sulpiride.

A time interval (more than 2 hours, if possible) should be maintained between administration of these agents and sulpiride.

Combinations to be taken into account

Other sedatives

Enhanced CNS depression. Due to impaired concentration ability, driving vehicles and operating machinery may be hazardous.

Antihypertensive agents

Increased risk of arterial hypotension, particularly orthostatic.

Beta-blockers used in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol)

See "Combinations requiring caution" for beta-blockers used in heart failure. Vasodilatory effect and risk of arterial hypotension, particularly postural (additive effect).

Dapoxetine

Risk of increased frequency of adverse effects, particularly dizziness or syncope.

Orlistat

Risk of ineffective treatment when used concomitantly with orlistat.

Special precautions for use.

In patients suffering from diabetes mellitus or having risk factors for developing diabetes, appropriate monitoring of blood glucose levels should be performed at the beginning of sulpiride therapy.

Except for specific cases, this medicinal product should not be prescribed to patients with Parkinson's disease.

For patients with renal impairment, reduced dosage and intensified monitoring are recommended; in cases of severe renal impairment, intermittent treatment courses are advisable.

Careful monitoring during sulpiride therapy is required in:

• patients with epilepsy, as sulpiride may lower the seizure threshold; cases of seizures have been reported in patients treated with sulpiride (see section "Adverse reactions");
• elderly patients, who are more susceptible to orthostatic hypotension, sedative effects, and extrapyramidal effects of the drug.

Leukopenia, neutropenia, and agranulocytosis have been reported during treatment with antipsychotics, including sulpiride. Infections of unknown etiology or unexplained fever may be signs of leukopenia (see section "Adverse reactions"); in such cases, a blood test should be performed immediately.

Potentially fatal neuroleptic malignant syndrome. Neuroleptic malignant syndrome—a potentially fatal complication reported during therapy with neuroleptics—is characterized by hyperthermia, pallor, autonomic nervous system disorders, altered consciousness, muscle rigidity, rhabdomyolysis, elevated serum creatine phosphokinase levels, and autonomic instability. Cases with atypical features, such as elevated body temperature without rigidity or hypertonia, have also been observed. In case of unexplained fever, which may be considered an early sign/symptom of neuroleptic malignant syndrome or atypical neuroleptic malignant syndrome, sulpiride and all other neuroleptics should be discontinued immediately under medical supervision.

Signs of autonomic nervous system dysfunction, such as excessive sweating and changes in blood pressure, may develop prior to hyperthermia and should therefore be considered as early warning symptoms.

Although this effect of neuroleptics may be idiopathic in nature, risk factors such as dehydration and organic brain damage may be present.

QT interval prolongation. Sulpiride may cause dose-dependent QT interval prolongation. This effect, known to increase the risk of serious ventricular arrhythmias, particularly bidirectional or torsades de pointes-type ventricular tachycardia, is more frequently observed in patients with bradycardia, hypokalemia, and congenital or acquired QT prolongation (when sulpiride is taken concomitantly with a medicinal product causing QT prolongation); see section "Adverse reactions."

Therefore, before initiating treatment and whenever clinically feasible, patients should be evaluated for risk factors that may predispose to this type of arrhythmia. Risk factors include: bradycardia less than 55 beats per minute, hypokalemia, congenital QT prolongation, use of a medicinal product that may cause marked bradycardia (less than 55 beats per minute), hypokalemia, slowed intracardiac conduction, or QT prolongation (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Except in emergency situations, it is recommended to perform an ECG during the initial evaluation of patients who are to receive neuroleptic therapy.

Stroke

During randomized, placebo-controlled clinical trials in elderly patients with dementia treated with certain atypical antipsychotics, an increased risk of stroke was observed. The mechanism of this increased risk is unknown. An increased risk with the use of other antipsychotic agents or in other patient populations cannot be ruled out. This medicinal product should be prescribed with caution to patients who have risk factors for stroke.

Elderly patients with dementia

The risk of mortality is increased in elderly patients with psychosis associated with dementia who are treated with antipsychotic agents.

An analysis of data from 17 placebo-controlled trials (with a mean duration of 10 weeks), involving patients treated with atypical antipsychotics, showed that the risk of death was 1.6–1.7 times higher in patients receiving these drugs compared to placebo.

After an average treatment duration of 10 weeks, the mortality risk was 4.5% in the treatment group compared to 2.6% in the placebo group.

Although the causes of death in clinical trials with atypical antipsychotics were varied, most fatalities were due to cardiovascular events (such as heart failure, sudden death) or infectious diseases (e.g., pneumonia).

Observational studies suggest that treatment with conventional antipsychotics may increase the likelihood of death similarly to atypical antipsychotics.

The relative contribution of the antipsychotic agent and patient characteristics to the increased mortality rate in observational studies remains unclear.

Venous thromboembolism (VTE). Rare fatal cases of venous thromboembolism (VTE) have been reported during treatment with antipsychotics. Since patients receiving antipsychotics often have acquired risk factors for VTE, all potential risk factors for VTE should be assessed before and during treatment, and preventive measures should be taken (see section "Adverse reactions").

Breast cancer. Since sulpiride may increase prolactin levels, it should be used with caution. Regardless of gender, all patients with a personal or family history of breast cancer require careful monitoring during sulpiride therapy.

Slowed intestinal peristalsis. Cases of intestinal obstruction have been reported in patients receiving antipsychotics. Rare cases of ischemic colitis and intestinal necrosis, sometimes fatal, have also been reported. Most patients were concurrently receiving one or more medicinal products that reduce gastrointestinal motility (including agents with anticholinergic properties). Particular attention should be paid to symptoms such as abdominal pain with vomiting and/or diarrhea. Constipation should be promptly recognized and actively treated. Development of paralytic or mechanical intestinal obstruction requires immediate medical intervention.

Even when used at low doses, the risk of developing tardive dyskinesia should be considered, particularly in elderly patients.

Concomitant use of this medicinal product with alcohol, levodopa, dopamine receptor agonists, antiparasitic agents that may cause torsades de pointes ventricular tachycardia, methadone, other neuroleptics, and medicinal products that may cause torsades de pointes ventricular tachycardia should be avoided (see section "Adverse reactions").

Since the efficacy and safety of sulpiride in children have not been fully established, caution is required when using this medicinal product (see section "Dosage and administration"). Due to the drug's effect on cognitive function, annual clinical assessments to evaluate learning ability are recommended. The dosage should be periodically adjusted based on the child's clinical status. The use of tablets in children under 6 years of age is contraindicated due to the risk of airway obstruction.

Sulpiride should be used with caution in patients with glaucoma, intestinal obstruction, congenital gastrointestinal stenosis, urinary retention, or a history of prostate hyperplasia.

Sulpiride should be used cautiously in patients predisposed to arterial hypertension, particularly elderly patients, due to the risk of hypertensive crisis. Therefore, appropriate monitoring of such patients is required.

Warning about excipients

Betamax tablets contain lactose. This medicinal product is not recommended for patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome (rare inherited disorders).

Use during pregnancy or breastfeeding.

Pregnancy.

In animal studies, reduced fertility associated with the pharmacological properties of the drug (prolactin-mediated effect) has been observed. There is very limited data on the use of sulpiride during pregnancy. The safety of sulpiride during pregnancy has not been established. Sulpiride crosses the placental barrier. Animal studies have shown reproductive toxicity. The use of sulpiride is not recommended in pregnant women and women of reproductive potential who are not using effective contraception, except when the expected benefit outweighs the potential risk.

Newborns whose mothers received antipsychotics during the third trimester of pregnancy are at risk of developing adverse reactions after birth, including extrapyramidal symptoms and/or withdrawal symptoms, with varying severity and duration. Adverse reactions reported include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory disorders, and feeding difficulties. Therefore, newborns should be closely monitored.

Period of breastfeeding.

Sulpiride is excreted in breast milk in relatively large amounts. In some cases, concentrations exceed 10% of the dose adjusted for maternal body weight. However, sulpiride concentrations in infant blood have not been measured. There is insufficient data on the effects of sulpiride on newborns and infants.

The decision to discontinue breastfeeding or to discontinue sulpiride therapy should be made considering the benefits of breastfeeding for the child and the benefits of treatment for the mother.

Ability to influence reaction speed when driving vehicles or operating machinery.

Patients, especially those who drive vehicles or operate machinery, should be warned that taking this medicinal product may cause somnolence (see section "Adverse reactions"). Driving vehicles and operating machinery are contraindicated during treatment with this medicinal product.

Method of Administration and Dosage

For oral use.

The lowest effective dose should always be prescribed. If the patient's clinical condition allows, treatment should be initiated with a low dose, followed by gradual dose titration as needed.

Adults. Short-term symptomatic treatment of anxiety states when usual therapeutic measures have not been effective: the daily dose is 50–150 mg for no longer than 4 weeks.

Children aged 6 years and older. Severe behavioral disorders (agitation, self-mutilation, stereotypy) in children aged 6 years and older, especially in patients with autistic syndromes: 5 mg/kg body weight per day (the dose may be increased, if necessary, up to 10 mg/kg body weight per day).

Children.

The use of tablets is contraindicated in children under 6 years of age.

Overdose.

Symptoms

Experience with sulpiride overdose is limited. Dystonic symptoms such as spasmodic torticollis, tongue protrusion, and trismus may occur. In some patients, life-threatening parkinsonism or even coma may develop. Fatal cases have been reported mainly following concomitant use of sulpiride with other psychotropic substances.

Treatment

Sulpiride is partially removed by hemodialysis. There is no specific antidote. Treatment should be symptomatic. Resuscitation measures with careful monitoring of cardiac and respiratory function (risk of QT interval prolongation and ventricular arrhythmias) must be maintained until full recovery. In case of severe extrapyramidal symptoms, anticholinergic agents should be administered.

Adverse reactions

Adverse reactions associated with the use of the medicinal product observed during clinical trials are listed below by organ system classes in decreasing order of frequency.

Blood and lymphatic system disorders

Uncommon: leucopenia.

Frequency not known: neutropenia, agranulocytosis.

Immune system disorders

Frequency not known: anaphylactic reactions such as urticaria, anaphylactic shock.

Endocrine disorders

Common: hyperprolactinaemia.

Psychiatric disorders

Common: insomnia.

Frequency not known: confusion.

Nervous system disorders

Common: sedative effect or drowsiness; extrapyramidal syndrome, which shows partial response to anticholinergic antiparkinsonian agents; parkinsonism; tremor; akathisia.

Uncommon: hypertonia, dyskinesia, dystonia.

Rare: oculogyric crisis.

Frequency not known: potentially fatal neuroleptic malignant syndrome (see section "Special precautions"), hypokinesia.

Tardive dyskinesia, which may occur during prolonged treatment with all neuroleptics; in this case antiparkinsonian drugs are ineffective and may worsen clinical symptoms.

Seizures (see section "Special precautions").

Metabolism and nutrition disorders

Frequency not known: hyponatraemia, inadequate secretion of antidiuretic hormone.

Cardiac disorders

Rare: ventricular arrhythmias, including paroxysmal torsades de pointes, ventricular tachycardia, which may lead to ventricular fibrillation or cardiac arrest.

Frequency not known: QT interval prolongation, sudden death (see section "Special precautions").

Vascular disorders

Uncommon: orthostatic hypotension.

Frequency not known: venous thromboembolism, including sometimes fatal cases of pulmonary artery embolism and deep vein thrombosis, increased blood pressure (see section "Special precautions").

Respiratory, thoracic and mediastinal disorders

Frequency not known: aspiration pneumonia (mainly when sulpiride is used concomitantly with other CNS depressants).

Gastrointestinal disorders

Common: constipation.

Uncommon: hypersalivation.

Hepatobiliary disorders

Common: increased liver enzyme activity.

Frequency not known: hepatocellular, cholestatic or mixed liver injury.

Musculoskeletal and connective tissue disorders

Frequency not known: rhabdomyolysis.

Skin and subcutaneous tissue disorders

Common: maculopapular rash.

Pregnancy, puerperium and perinatal period

Frequency not known: withdrawal syndrome in newborns (see section "Use during pregnancy or lactation").

Reproductive system and breast disorders

Common: galactorrhoea.

Uncommon: amenorrhoea, impotence or frigidity.

Frequency not known: gynaecomastia.

General disorders

Common: weight gain.

Frequency not known: increased body temperature (see section "Special precautions").

Investigations

Frequency not known: increased blood creatine phosphokinase concentration.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the adverse reaction reporting system in Ukraine at the following link: https://aisf.dec.gov.ua

Shelf life: 5 years.

Do not use after the expiry date stated on the packaging.

Storage conditions:

No special storage conditions required.

Keep out of the reach and sight of children.

Packaging:

10 tablets per blister; 3 blisters per cardboard pack.

Prescription status:

Prescription only.

Manufacturer:

JSC "Grindeks"

Address of manufacturer and location of its business activities:

53 Krustpils Street, Riga, LV-1057, Latvia.

Tel./fax: +371 67083205 / +371 67083505

E-mail: [email protected]