Sulpiride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Sulpiride (Sulpiryd)

Composition:

Active substance: sulpiride;

1 capsule contains 50 mg or 100 mg of sulpiride;

Excipients: colloidal anhydrous silicon dioxide, corn starch, lactose monohydrate, magnesium stearate;

Hard gelatin capsule for 50 mg: gelatin, titanium dioxide (E 171);

Hard gelatin capsule for 100 mg: gelatin, titanium dioxide (E 171), quinoline yellow (E 104), iron oxide red (E 172).

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

50 mg capsules: cylindrical capsules with semi-rounded edges, size 3, white in color, filled with white or cream-colored powder;

100 mg capsules: cylindrical capsules with semi-rounded edges, size 3, yellow in color, filled with white or cream-colored powder.

Pharmacotherapeutic group. Antipsychotic agents. Benzamides. ATC code N05A L01.

Pharmacological properties.

Pharmacodynamics.

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

Sulpiride increases prolactin secretion. The active substance improves mucus secretion and blood supply to the mucous membrane of the stomach and duodenum.

Sulpiride also demonstrates antiemetic activity.

Pharmacokinetics.

Sulpiride is slowly absorbed from the gastrointestinal tract. The presence of food reduces absorption by 30%. Bioavailability is low (27–34%) and depends on individual differences. The active substance rapidly distributes into tissues; only a small amount crosses the blood-brain barrier. Maximum plasma concentration is reached within 3–6 hours after oral administration. Protein binding is approximately 40%, and the volume of distribution ranges from 1 to 2.7 L/kg. The elimination half-life from plasma is about 8 hours. In patients with severe renal impairment, it is prolonged to 20–26 hours after intravenous administration. A small amount of the active substance passes into breast milk. It is excreted in urine and feces predominantly in unchanged form.

Clinical characteristics.

Indications.

Short-term symptomatic treatment of anxiety disorders in adults when usual therapeutic measures have not been effective.

Severe behavioural disorders (agitation, self-mutilation, 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.
• Known or suspected diagnosis of phaeochromocytoma.
• Acute porphyria.
• Concomitant prolactin-dependent tumours (e.g. prolactin-secreting pituitary adenoma (prolactinoma) and breast cancer).
• Concomitant use with dopamine receptor agonists not used for the treatment of Parkinson's disease (cabergoline, quinagolide), levodopa, citalopram and escitalopram, hydroxyzine, domperidone, and piperazine (see section "Interaction with other medicinal products and other forms of interaction").
• Breastfeeding (see section "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Sedatives

It should be remembered that many medicinal products or substances may have additive central nervous system depressant effects and reduce mental performance. These include morphine derivatives (analgesics, antitussives, and substitution therapy agents), 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.

Medicinal products that may induce 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" below) and bradycardia (see "Agents causing bradycardia" below), or the presence of congenital or acquired QT interval prolongation.

Such agents include, in particular, class Ia and III antiarrhythmics and some neuroleptics. This effect may also be induced by other agents not belonging to these classes.

This interaction occurs with dolasetron, erythromycin, spiramycin, and vinca alkaloids, but only in intravenous formulations.

Concomitant administration of two "torsadogenic" (inducing torsades de pointes) agents is generally contraindicated. However, some of these agents are exceptions, as their use cannot always be avoided. Therefore, they are simply 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 among these exceptions: their concomitant use with all agents that may induce torsades de pointes is contraindicated.

Contraindicated combinations (see section "Contraindications")

Citalopram, escitalopram

Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Non-Parkinson's disease dopamine receptor agonists (cabergoline, quinagolide)

Mutual antagonism exists between dopamine agonists and neuroleptics.

Domperidone

Increased risk of ventricular arrhythmia, particularly torsades de pointes.

Hydroxyzine

Increased risk of ventricular arrhythmia, particularly torsades de pointes.

Piperaquine

Increased risk of ventricular arrhythmia, particularly torsades de pointes.

Undesirable combinations (see section "Special precautions for use")

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

Due to increased risk of ventricular arrhythmias, particularly torsades de pointes, one of the two agents should be discontinued if possible. If concomitant treatment cannot be avoided, QT interval should be checked before initiation and ECG monitoring should be performed during treatment.

Anti-Parkinson's dopamine agonists (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, ropinirole, rasagiline, 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, dopamine agonist doses should be gradually reduced (abrupt withdrawal increases the risk of neuroleptic malignant syndrome).

Other agents that may induce torsades de pointes (class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide) and class III (amiodarone, dronedarone, sotalol, dofetilide, ibutilide) and other agents such as arsenic compounds, difemethadine, 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 torsades de pointes.

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

High risk of ventricular arrhythmias, particularly torsades de pointes.

Alcohol (beverage or excipient)

Potentiation of sedative effects of neuroleptic agents.

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

Patients should avoid alcoholic beverages or medicinal products containing alcohol.

Levodopa

Mutual antagonism exists between levodopa and neuroleptics.

Patients with Parkinson's disease receiving both dopamine agonists and neuroleptics should be prescribed the lowest effective doses of both agents.

Methadone

Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Combinations requiring caution

Anagrelide

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

Azithromycin

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

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

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

Agents causing bradycardia (including class Ia antiarrhythmics, beta-blockers, some class III antiarrhythmics, certain calcium channel blockers, crizotinib, digitalis glycosides, pasireotide, pilocarpine, cholinesterase inhibitors)

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

Ciprofloxacin, levofloxacin, norfloxacin

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

Clarithromycin

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

Potassium-sparing agents (potassium-sparing diuretics, including combinations, stimulant laxatives, glucocorticoids, tetracosactide, and intravenous amphotericin B)

Increased risk of ventricular arrhythmias, particularly torsades de pointes.

Any existing hypokalaemia should be corrected before administration, and clinical monitoring, electrolyte level checks, and ECG monitoring should be performed.

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, one of the two agents should be discontinued.

Ondansetron

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

Roxithromycin

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

Sucralfate

Reduced gastrointestinal absorption of sulpiride.

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

Locally-acting gastrointestinal agents, antacids, and activated charcoal

Reduced gastrointestinal absorption of sulpiride.

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

Combinations with warnings

Other sedative agents

More pronounced central nervous system depression. Due to impaired concentration ability, driving vehicles and operating machinery may be hazardous.

Antihypertensive agents

Increased risk of arterial hypotension, particularly postural hypotension.

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

See "Combinations requiring caution" above. Vasodilatory effect and increased risk of arterial hypotension, particularly postural (additive effect).

Dapoxetine

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

Orlistat

Risk of reduced treatment efficacy when used concomitantly with orlistat.

Special precautions for use.

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

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

As with other medicinal products that are primarily eliminated via the kidneys, dose reduction and intensified monitoring are recommended in patients with renal impairment; in cases of severe renal insufficiency, intermittent treatment courses are advisable.

During sulpiride therapy, closer observation is required for:

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

Cases of leukopenia, neutropenia, and agranulocytosis have been reported during treatment with antipsychotics, including sulpiride. Unexplained infections or sore throat may indicate blood dyscrasia and require immediate blood laboratory testing.

Potentially fatal neuroleptic malignant syndrome. In case of unexplained fever, treatment must be discontinued immediately, as this may be one of the symptoms of a malignant syndrome that may develop during treatment with neuroleptics (pallor, hyperthermia, autonomic dysfunction, altered consciousness, muscle rigidity).

Signs of autonomic nervous system dysfunction, such as increased sweating and changes in blood pressure, may precede the onset of 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 provoke QT interval prolongation. This increases the risk of developing serious ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the torsades de pointes type, which is more frequently observed in patients with bradycardia, hypokalemia, and congenital or acquired QT interval prolongation (especially when sulpiride is taken concomitantly with a medicinal product that causes QT interval prolongation) (see section "Adverse reactions").

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

Except in emergency situations, ECG examination is recommended during initial assessment of patients who require neuroleptic treatment. Concomitant use of sulpiride with other neuroleptics should be avoided.

Stroke. In randomized, placebo-controlled clinical trials in elderly patients with dementia treated with certain atypical antipsychotics, an increased risk of stroke was observed compared to those receiving placebo. The mechanism of this increased risk is unknown. An increased risk with other antipsychotics or in other patient groups 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 fatal outcome is increased in elderly patients suffering from psychosis associated with dementia who are treated with antipsychotics.

Analysis of data from studies involving patients generally taking atypical antipsychotics showed that the risk of death was 1.6 to 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 causes of fatal outcomes with atypical antipsychotics were varied, most occurred due to cardiovascular diseases (e.g., heart failure, sudden death) or infections (e.g., pneumonia).

Epidemiological studies suggest that treatment with typical antipsychotics may also increase mortality, similar to atypical antipsychotics.

The relative contribution of the antipsychotic drug versus patient characteristics to the increased mortality rate in epidemiological studies remains unclear.

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

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

Reduced intestinal motility. 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 of these patients were concurrently receiving one or more medicinal products that provoke reduced intestinal motility (particularly agents with anticholinergic properties). Particular attention should be paid to the onset of abdominal pain with vomiting and/or diarrhea. Early recognition and active treatment of constipation are very important. Development of paralytic or mechanical intestinal obstruction requires immediate treatment.

This medicinal product should not be taken concomitantly with alcohol, levodopa, dopamine receptor agonists, antiparasitic agents that may provoke torsades de pointes, methadone, other neuroleptics, or medicinal products that may provoke torsades de pointes (see section "Interaction with other medicinal products and other forms of interaction").

Sulpiride has anticholinergic effects; therefore, it should be used with caution in patients with glaucoma, intestinal obstruction, congenital stenosis of the gastrointestinal tract, urinary retention, or a history of prostate hyperplasia.

Sulpiride should be used with caution in patients with arterial hypertension, particularly elderly patients, due to the risk of hypertensive crisis. Close monitoring of the patient's condition is required.

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

Sulpiride should not be taken late in the evening, as it may disturb sleep.

This medicinal product contains lactose and therefore should not be used in patients with galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome (rare hereditary conditions).

Use during pregnancy or breastfeeding.

Pregnancy. In animal studies, reduced fertility associated with the pharmacological properties of sulpiride (prolactin-mediated effect) has been observed. Animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonic/fetal development, or postnatal development. Very limited data are available in humans regarding effects on pregnancy. In almost all reported cases of fetal or neonatal developmental abnormalities associated with sulpiride use during pregnancy, alternative explanations appear more likely. Therefore, due to limited experience with sulpiride use during pregnancy, its use is not recommended. Neonates whose mothers received antipsychotics (including sulpiride) during the third trimester of pregnancy may experience adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, with varying severity and duration. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress syndrome, and feeding difficulties have been reported. Therefore, careful monitoring of neonates is required.

Breastfeeding. Since sulpiride is excreted in breast milk, breastfeeding during treatment is not recommended.

Ability to affect reaction speed when driving or operating machinery.

Patients, especially those who drive vehicles or operate machinery, should be warned that use of this medicinal product may cause somnolence (see section "Adverse reactions"). Driving vehicles or operating machinery is 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 start with a low dose, followed by gradual dose titration.

Sulpiride should be taken at least 1 hour before or 2 hours after a meal.

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

Children aged 6 years and older. Severe behavioral disorders (agitation, self-mutilation, stereotypy), particularly in patients with autistic syndromes: 5 mg/kg body weight per day (if necessary, this dose may be increased up to 10 mg/kg body weight per day). For children, another dosage form—oral solution—is more suitable.

Patients with renal impairment. For this patient group, the dose should be adjusted according to the degree of renal function impairment: either reduce the dose or prolong the dosing interval.

Children.

Since the efficacy and safety of sulpiride in children have not been fully established, it should be used with caution (see section "Method of Administration and Dosage"). Due to the drug's effect on cognitive abilities, annual clinical evaluations are recommended to assess learning capacity. The dosage should be periodically adjusted based on the child’s clinical status.

The use of hard capsules in children under 6 years of age is contraindicated, as this may lead to airway obstruction.

Overdose.

Experience with sulpiride overdose is limited. Dystonic symptoms may occur, including spasmodic torticollis, tongue protrusion, and trismus. In some patients, life-threatening parkinsonism or even coma may develop.

Fatal cases have mainly been reported following concomitant use with other psychotropic drugs.

Sulpiride is partially removed by hemodialysis. There is no specific antidote for sulpiride.

Treatment should be symptomatic: resuscitation with careful monitoring of cardiac function and respiration (risk of QT interval prolongation and ventricular arrhythmias), which should continue until full recovery. In case of severe extrapyramidal syndrome, anticholinergic agents should be administered.

Adverse Reactions

Adverse reactions are categorized by frequency as follows: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders

Uncommon: leucopenia.

Frequency not known: neutropenia, agranulocytosis.

Immune system disorders

Frequency not known: anaphylactic reactions (urticaria, anaphylactic shock).

Endocrine system disorders

Common: hyperprolactinaemia.

Psychiatric disorders

Common: insomnia.

Frequency not known: confusion.

Nervous system disorders

Common: sedative effect or drowsiness; extrapyramidal syndrome, which is partially reversible with administration of anticholinergic anti-Parkinson agents; parkinsonism; tremor; akathisia.

Uncommon: hypertonia, dyskinesia, dystonia.

Rare: oculogyric crisis.

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

Tardive dyskinesia, which may occur during prolonged treatment with all neuroleptics; in such cases, anti-Parkinson drugs are ineffective and may worsen clinical manifestations.

Seizures (see section "Special precautions for use").

Metabolism and nutrition disorders

Frequency not known: hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion.

Cardiac disorders

Rare: ventricular arrhythmias, such as paroxysmal torsades de pointes tachycardia and ventricular tachycardia, which may result in ventricular fibrillation or cardiac arrest.

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

Vascular disorders

Uncommon: orthostatic hypotension.

Frequency not known: venous thromboembolism, pulmonary artery embolism, deep vein thrombosis, increased blood pressure (see section "Special precautions for use").

Respiratory, thoracic and mediastinal disorders

Frequency not known: aspiration pneumonia (mainly when sulpiride is used concomitantly with other central nervous system 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

Rare: spasmodic torticollis, trismus.

Skin and subcutaneous tissue disorders

Common: maculopapular rash.

Pregnancy, postpartum and perinatal conditions

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

Reproductive system and breast disorders

Common: galactorrhoea.

Uncommon: amenorrhoea, impotence or frigidity.

Frequency not known: gynaecomastia.

General disorders

Common: weight gain.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C, in a place inaccessible to children.

Packaging. 12 capsules in a blister, 2 blisters per carton.

Prescription category. Prescription only.

Manufacturer. Teva Operations Poland Sp. z o.o.

Manufacturer's address and place of business.
80 Mogilska Street, 31-546 Kraków, Poland