Sulpiride

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

Composition:

Active ingredient: sulpiride;

1 tablet contains 200 mg of sulpiride;

Excipients: lactose monohydrate, corn starch, povidone, microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets, odorless, with a bitter taste, round-shaped, biconvex, with a smooth surface free from spots and chips.

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

Pharmacological properties.

Pharmacodynamics.

Sulpiride belongs to the group of substituted benzamides and is structurally different from phenothiazines, butyrophenones, and thioxanthenes.

In terms of effects on behavior and biochemistry, sulpiride shares certain properties with classical neuroleptics, indicating antagonism towards dopamine receptors in the brain. Key differences include the absence of a cataleptic effect at therapeutically effective doses, no influence on noradrenaline and serotonin (5-HT) metabolism, minimal anticholinesterase activity, and no effect on muscarinic receptors or gamma-aminobutyric acid (GABA) receptors. One characteristic feature of sulpiride is its bimodal activity, as it exhibits both antidepressant and antipsychotic properties. Improvement in mood is observed within several days of treatment, followed by a reduction in prominent symptoms of schizophrenia. Sedative effects and emotional blunting, commonly associated with classical phenothiazine- or butyrophenone-type neuroleptics, are not typical features of sulpiride therapy.

The therapeutic effect in the treatment of schizophrenia becomes evident 8–12 weeks after initiation of treatment.

Sulpiride stimulates prolactin secretion. The drug enhances mucus secretion and improves blood supply to the gastric and duodenal mucosa.

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, this is prolonged to 20–26 hours after intravenous administration. A small amount of the active substance is excreted into breast milk. The drug is primarily excreted unchanged in urine and feces.

Clinical characteristics.

Indications.

Acute mental disorders. Chronic mental disorders (schizophrenia, chronic non-schizophrenic disorders: paranoid states, chronic hallucinatory psychosis).

Contraindications.

• Hypersensitivity to sulpiride or any of the excipients of the medicinal product.
• Known or suspected diagnosis of pheochromocytoma.
• 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), citalopram, 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.

Sedative agents

It should be remembered that many medicinal products or substances may have additive central nervous system depressant effects and reduce mental activity. 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 paroxysmal ventricular tachycardia (torsades de pointes)

This serious cardiac arrhythmia may be caused by several medicinal products, with or without antiarrhythmic activity. Predisposing 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.

Dolasetron, erythromycin, spiramycin, and vinca alkaloids – only in intravenous formulations – are involved in such interactions.

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 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 paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes).

Agonists of dopamine receptors not used 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 torsades de pointes-type ventricular tachycardia (torsades de pointes).

Hydroxyzine

Increased risk of ventricular arrhythmia, particularly paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes).

Piperaquine

Increased risk of ventricular arrhythmia, particularly paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes).

Not recommended combinations (see section "Special warnings and precautions for use")

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

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

Antiparkinsonian 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 existing psychiatric disorders. In patients with Parkinson's disease receiving dopamine agonist therapy who require neuroleptic treatment, dopamine agonist doses should be gradually reduced and discontinued (abrupt withdrawal may precipitate neuroleptic malignant syndrome).

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

High risk of ventricular arrhythmias, particularly paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes).

Other neuroleptics that may induce paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes) ( amisulpride, chlorpromazine, tiaramide, droperidol, flupentixol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazide, sulpiride, tiapride, zuclopenthixol)

High risk of ventricular arrhythmias, particularly paroxysmal torsades de pointes-type ventricular tachycardia (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 consuming 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 minimum effective doses of both agents.

Methadone

Increased risk of ventricular arrhythmias, particularly paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes).

Combinations requiring caution

Anagrelide

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

Azithromycin

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

Agents causing bradycardia (e.g. class Ia antiarrhythmics, beta-blockers, some class III antiarrhythmics, certain calcium channel blockers, crizotinib, digoxin, pasireotide, pilocarpine, anticholinesterase agents)

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

Ciprofloxacin, levofloxacin, norfloxacin

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

Clarithromycin

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

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

Increased risk of ventricular arrhythmias, particularly paroxysmal torsades de pointes-type ventricular tachycardia (torsades de pointes).

Any existing hypokalaemia should be corrected prior to administration. Clinical monitoring, electrolyte level checks, 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. Discontinuation of one of the two agents is recommended upon first signs of neurotoxicity.

Ondansetron

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

Roxithromycin

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

Sucralfate

Reduced gastrointestinal absorption of sulpiride.

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

Locally acting gastrointestinal agents, antacids, and activated charcoal

Reduced gastrointestinal absorption of sulpiride.

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

Combinations with warnings

Other sedative agents

Enhanced 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 for beta-blockers used in heart failure. 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 efficacy of treatment 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 primarily excreted by the kidneys, dose reduction and intensified monitoring are recommended for patients with renal impairment; in cases of severe renal impairment, intermittent treatment courses are advisable.

During sulpiride therapy, closer observation is required for:

• Patients with epilepsy, as 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 pharyngitis 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 nervous system disorders, impaired consciousness, muscle rigidity).

Signs of autonomic nervous system dysfunction, such as increased sweating and blood pressure changes, may precede the onset of hyperthermia and should therefore be considered as early warning signs.

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 administration may provoke QT interval prolongation. This increases the risk of developing serious ventricular arrhythmias, particularly paroxysmal torsades de pointes-type ventricular tachycardia, more frequently observed in patients with bradycardia, hypokalemia, and congenital or acquired QT interval prolongation (when sulpiride is taken concomitantly with a medicinal product causing 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 use of medicinal products that may cause marked bradycardia (less than 55 beats per minute), hypokalemia, slowed 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 the initial assessment of patients requiring neuroleptic treatment. Concomitant use of sulpiride with other neuroleptics is not recommended.

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 excluded. 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 and receiving antipsychotic treatment.

Analysis of data from 17 placebo-controlled studies (with a mean duration of 10 weeks) involving patients generally treated with atypical antipsychotics showed that the risk of death was increased by 1.6–1.7 times in patients receiving these drugs compared to placebo. After a mean treatment period 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 fatal outcomes with atypical antipsychotics varied, most deaths resulted from cardiovascular diseases (e.g., heart failure, sudden death) or infections (e.g., pneumonia).

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

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

Venous thromboembolism. Cases of venous thromboembolism (VTE) have been reported during antipsychotic treatment. 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. 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 treatment.

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 causing reduced intestinal motility (particularly those 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.

Concomitant use of this medicinal product with alcohol, levodopa, dopamine receptor agonists, antiparasitic agents that may provoke torsades de pointes-type ventricular tachycardia, methadone, other neuroleptics, and medicinal products that may cause torsades de pointes-type ventricular tachycardia is not recommended (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, especially elderly patients, due to the risk of hypertensive crisis. Therefore, appropriate monitoring of such patients is required.

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 related to the pharmacological properties of the drug (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. Data in humans regarding the effect on pregnancy are very limited. In almost all reported cases of fetal or neonatal 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 drowsiness (see section "Adverse reactions"). Driving vehicles or operating machinery is contraindicated during treatment with this drug.

Dosage and method of administration

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.

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

This medicinal product in this pharmaceutical form is intended for adults only.

The daily dose is 200–1000 mg.

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

Children.

The use of this medicinal product in this pharmaceutical form is not recommended in children.

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 been reported mainly following administration of sulpiride in combination with other psychotropic agents.

Sulpiride is partially eliminated 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 be maintained 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 (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); 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, dyspnea, hypotension, anaphylactic shock).

Endocrine system disorders

Common: hyperprolactinemia.

Psychiatric disorders

Common: insomnia.

Frequency not known: confusion.

Nervous system disorders

Common: sedative effect or drowsiness; extrapyramidal symptoms, which partially respond to anticholinergic antiparkinsonian agents; parkinsonism; tremor; hyperkinetic-hypertonic, agitated motor activity; 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 such cases, anticholinergic antiparkinsonian drugs are ineffective and may worsen clinical symptoms.

Seizures (see section "Special precautions").

Metabolism and nutrition disorders

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

Cardiac disorders

Rare: ventricular arrhythmias such as paroxysmal torsades de pointes tachycardia and 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, pulmonary artery embolism, 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 central nervous system depressants).

Gastrointestinal disorders

Common: constipation.

Uncommon: hypersalivation.

Hepatobiliary disorders

Common: increased liver enzyme activity.

Frequency not known: cholestatic or mixed hepatitis.

Musculoskeletal and connective tissue disorders

Rare: spasmodic torticollis, trismus.

Skin and subcutaneous tissue disorders

Common: maculopapular rash.

Pregnancy, postnatal and perinatal conditions

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

Reproductive system and breast disorders

Common: galactorrhea.

Uncommon: amenorrhea, impotence or frigidity.

Frequency not known: gynecomastia.

General disorders

Common: weight gain.

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C. Keep out of reach of children.

Packaging. 12 tablets in a blister pack, 1 blister per carton. 15 tablets in a blister pack, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer. TEVA Operations Poland Sp. z o.o.

Manufacturer's address.
80 Mogilska Street, 31-546 Kraków, Poland.