Restful

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RESTFUL (RESTFUL®)

Composition:

Active substance: sulpiride;

100 mg of sulpiride in 2 ml of solution;

Excipients: sulfuric acid, sodium chloride, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical characteristics: clear, almost colorless solution.

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 high doses, sulpiride has anti-prolactogenic activity.

Pharmacokinetics.

After intramuscular administration of a 100 mg dose, the maximum plasma concentration of sulpiride is reached within 30 minutes and amounts to 2.2 mg/L. Sulpiride rapidly distributes into body tissues; the apparent volume of distribution at steady state is 0.94 L/kg. Plasma protein binding of sulpiride is 40%. It passes in small amounts into breast milk and is able to cross the placental barrier. Sulpiride is practically not metabolized in the human body; 92% of the administered dose is excreted unchanged in the urine following intramuscular injection. It is primarily eliminated by the kidneys via glomerular filtration. Renal clearance is 126 mL/min. The elimination half-life from plasma is 7 hours.

Clinical characteristics.

Indications.

Short-term treatment of states of agitation and aggression in patients with acute and chronic mental disorders (schizophrenia, chronic delirium of non-schizophrenic origin: paranoid delusion, chronic hallucinatory psychosis).

Contraindications.

Hypersensitivity to sulpiride or to any of the excipients of the medicinal product (see section "Composition").

Prolactin-dependent tumours (e.g. prolactin-secreting pituitary adenoma (prolactinoma) and breast cancer).

Known or suspected diagnosis of phaeochromocytoma.

Acute porphyria.

Combinations with non-antiparkinsonian dopamine agonists (cabergoline, rotigotine, and quinagolide), with levodopa or antiparkinsonian medicinal products (including ropinirole), domperidone, hydroxyzine, piperazine, methiotazine, citalopram, and escitalopram (see section "Interaction with other medicinal products and other forms of interaction").

The medicinal product in this pharmaceutical form is intended only for adult patients.

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 may lead to reduced mental alertness. These 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, centrally acting antihypertensives (clonidine), baclofen, and thalidomide.

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

This serious cardiac arrhythmia may be caused by certain medicinal products, whether or not they have antiarrhythmic activity. Provocative factors include hypokalaemia (see "Potassium-sparing agents") and bradycardia (see "Agents causing bradycardia"), or the presence of congenital or acquired QT interval prolongation.

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

Dolasetron, erythromycin, spiramycin, and vinca alkaloids are included in this interaction only in intravenous formulations.

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

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

However, citalopram and escitalopram are not 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, methiotazine

Increased risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type.

Non-parkinsonian dopamine receptor agonists (cabergoline, quinagolide, rotigotine)

Mutual antagonism exists between dopamine agonists and neuroleptics.

Levodopa

Mutual antagonism exists between levodopa and neuroleptics.

Patients with Parkinson's disease receiving treatment with dopamine agonists and neuroleptics should be prescribed the minimum effective doses of both medicinal products.

Domperidone

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

Hydroxyzine

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

Piperaquine

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

Methiotazine

Increased risk of ventricular arrhythmias, particularly polymorphic ventricular tachycardia.

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

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

Increased risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type. If possible, antifungal azole treatment should be discontinued.

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

Antiparkinsonian dopamine agonists (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, ropinirole, ropagiline, selegiline)

Mutual antagonism exists between dopamine agonists and neuroleptics.

Dopamine agonists may induce or exacerbate psychiatric disorders. If neuroleptics are required in patients with Parkinson's disease receiving dopamine agonist therapy, the doses of dopamine agonists should be gradually reduced (abrupt withdrawal may lead to the development of neuroleptic malignant syndrome).

Other medicinal products 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 bepridil, cisapride, difemanil, intravenous dolasetron, domperidone, intravenous erythromycin, hydroxychloroquine, levofloxacin, methiotazine, mizolastine, prucalopride, intravenous vinca alkaloids, moxifloxacin, intravenous spiramycin, torasemide, and vandetanib).

High risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type.

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

High risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type.

Alcohol (beverage or excipient)

Potentiation of sedative effects of neuroleptics.

Due to impaired ability to concentrate, driving and operating machinery may be hazardous. Patients should avoid consumption of alcoholic beverages or use of medicinal products containing alcohol.

Levodopa

Mutual antagonism exists between levodopa and neuroleptics.

Patients with Parkinson's disease receiving treatment with dopamine agonists and neuroleptics should be prescribed the minimum effective doses of both medicinal products.

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 medicinal products is recommended.

Metadone

Increased risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type.

Combinations requiring caution.

Anagrelide

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

Azithromycin

Increased risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type. 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 paroxysmal ventricular tachycardia of the "torsades de pointes" type. 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, cardiac glycosides, pasireotide, pilocarpine, anticholinesterase agents).

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

Cyprofloxacin, levofloxacin, norfloxacin

Increased risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type. 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.

Hydroxyzine

Increased risk of ventricular arrhythmia, particularly torsades de pointes. ECG and clinical monitoring 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 paroxysmal ventricular tachycardia of the "torsades de pointes" type. Correction of existing hypokalaemia should be performed prior to administration, and clinical monitoring and electrolyte and ECG control should be maintained.

Ondansetron

Increased risk of ventricular arrhythmias, particularly paroxysmal ventricular tachycardia of the "torsades de pointes" type. 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.

Other sedatives

Enhanced central nervous system depression. Due to impaired ability to concentrate, driving and operating machinery may be hazardous.

With 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 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 medicinal products.

Combinations to be considered

Antihypertensive agents

Increased risk of arterial hypotension, particularly orthostatic hypotension.

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

Vasodilatory effect and risk of 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.

Nitrates, nitrites, and related agents

Increased risk of hypotension, particularly postural.

Lithium use increases the risk of extrapyramidal adverse effects.

Sulpiride may reduce the efficacy of ropinirole.

Special precautions for use.

Cases of hyperglycemia have been reported in patients treated with atypical antipsychotics. Therefore, appropriate monitoring of blood glucose levels should be performed at the beginning of sulpiride therapy in patients with diabetes mellitus or those with risk factors for developing diabetes.

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

Dosage reduction and intensified monitoring are recommended for patients with renal impairment. In cases of severe renal impairment, intermittent treatment courses are advisable.

Careful monitoring is required during sulpiride therapy 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 susceptible to orthostatic hypotension, sedative effects, and extrapyramidal effects of the drug.

Sulpiride should be administered together with sedative agents in patients with aggressive behavior or agitation with impulsivity.

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 count should be performed immediately.

Potentially fatal Neuroleptic Malignant Syndrome (NMS).

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

Signs of autonomic dysfunction, such as excessive sweating and changes in blood pressure, may precede the onset of hyperthermia and should therefore be considered early warning symptoms. Although this effect of neuroleptic agents may be idiosyncratic, 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 may increase the risk of serious ventricular arrhythmias, including torsades de pointes ventricular tachycardia, which is more frequently observed in patients with bradycardia, hypokalemia, or congenital or acquired QT prolongation (especially when sulpiride is used concomitantly with another drug that prolongs the QT interval) (see section "Adverse reactions").

Therefore, before initiating treatment with this drug, and if clinically feasible, the presence of risk factors predisposing to this type of arrhythmia should be assessed: heart rate less than 55 beats per minute, hypokalemia, congenital QT prolongation, or concomitant use of drugs 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, it is recommended to perform an ECG during the initial evaluation of patients who are to receive neuroleptic therapy.

Stroke

In clinical trials involving 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 the use of other antipsychotics or in other patient populations cannot be ruled out. This medicinal product should be used with caution in patients with 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 drugs.

An analysis of data from studies (with a mean duration of 10 weeks) involving patients treated with 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 period of 10 weeks, the mortality rate 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 varied, most deaths were due to cardiovascular (e.g., heart failure, sudden death) or infectious conditions (e.g., pneumonia). Observational studies suggest that treatment with conventional antipsychotics may increase mortality similarly to atypical antipsychotics.

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

Venous thromboembolism (VTE)

Fatal cases of venous thromboembolism (VTE) have been reported during antipsychotic therapy. Since patients treated with antipsychotics often have acquired risk factors for VTE, all potential risk factors for VTE should be assessed before and during treatment with Restful, 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 sex, all 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 treated with antipsychotics. Rare cases of ischemic colitis and intestinal necrosis, sometimes fatal, have also been reported. Most patients were concurrently receiving one or more drugs that reduce gastrointestinal motility (particularly drugs 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. The development of paralytic or mechanical intestinal obstruction requires immediate medical intervention.

When using this medicinal product, even 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 "Interaction with other medicinal products and other forms of interaction").

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

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

This medicinal product contains sodium (30 mg of sodium per dose). This should be taken into account in patients on a strictly low-sodium diet.

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. There is very limited data on the use of sulpiride during pregnancy. The safety of sulpiride use during pregnancy has not been established. Sulpiride crosses the placental barrier. Animal studies have shown reproductive toxicity. Sulpiride is not recommended for use in pregnant women or women of childbearing potential who are not using effective contraception, except when the expected benefits of sulpiride treatment outweigh the potential risks. Intravenous administration of neuroleptics may lead to hypotension in pregnant women.

Newborns whose mothers received antipsychotics during the third trimester of pregnancy are at risk of developing adverse effects, including extrapyramidal syndrome and/or withdrawal symptoms, with varying severity and duration. Adverse reactions reported include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress syndrome, and feeding difficulties. Therefore, careful monitoring of the newborn is required.

Lactation

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 determined. 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 infant and the benefits of continuing treatment for the mother.

Ability to influence reaction speed when driving or operating machinery.

Patients, especially those who drive vehicles or operate machinery, should be warned that the use of Restful may cause somnolence (see section "Adverse reactions"). The use of this medicinal product is contraindicated during driving and while operating machinery.

Method of Administration and Dosage

The medicinal product should be administered intramuscularly.

This medicinal product is intended only for adult patients.

Always prescribe the lowest effective dose. If the patient's clinical condition allows, treatment should be initiated at a low dose (100 mg), followed by gradual dose titration if necessary.

The dose is 400 mg to 800 mg per day for a period of 2 weeks.

After opening the ampoule, the medicinal product should be used immediately.

Children

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

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 primarily following administration of sulpiride in combination with other psychotropic substances.

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

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

Adverse Reactions

Blood and lymphatic system disorders

Uncommon: leucopenia.

Frequency unknown: neutropenia, agranulocytosis.

Immune system disorders

Frequency unknown: anaphylactic reactions, urticaria, anaphylactic shock.

Endocrine system disorders

Common: hyperprolactinemia.

Psychiatric disorders

Common: insomnia.

Frequency unknown: confusion.

Nervous system disorders

Common: sedative effect or drowsiness; extrapyramidal symptoms responding partially to anticholinergic anti-Parkinson agents; parkinsonism; tremor, hypertonia, hypokinesia, hypersalivation;

• akinetic symptoms, with or without hypertonia, partially responsive to anticholinergic anti-Parkinson agents;
• hyperkinetic-hypertonic, agitated motor activity;
• akathisia.

Uncommon: hypertonia, dyskinesia, dystonia.

Rare: oculogyric crisis.

Frequency unknown: potentially fatal neuroleptic malignant syndrome (see section "Special precautions"); hypokinesia.

Tardive dyskinesia, characterized by involuntary rhythmic movements, particularly of the tongue and/or face, which may occur during prolonged treatment with all neuroleptics; in this case, anticholinergic anti-Parkinson drugs are ineffective and may worsen clinical manifestations.

Seizures (see section "Special precautions").

Early dyskinesia (spasmodic torticollis, oculogyric crises, trismus), which improves with anticholinergic anti-Parkinson agents.

Insomnia and confusion.

Metabolic and nutritional disorders

Frequency unknown: hyponatremia, inadequate antidiuretic hormone secretion.

Cardiac disorders

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

Frequency unknown: QT interval prolongation, sudden fatal outcome (see section "Special precautions").

Vascular disorders

Uncommon: orthostatic hypotension.

Frequency unknown: 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 unknown: 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 unknown: hepatocellular, cholestatic, or mixed liver injury.

Musculoskeletal and connective tissue disorders

Frequency unknown: rhabdomyolysis.

Skin and subcutaneous tissue disorders

Common: maculopapular rash.

Pregnancy, postpartum and perinatal period

Frequency unknown: withdrawal syndrome in newborns (see section "Use during pregnancy or breastfeeding").

Reproductive system and breast disorders

Common: galactorrhea.

Uncommon: amenorrhea, impotence or frigidity.

Frequency unknown: gynecomastia.

General disorders and administration site conditions

Common: weight gain.

Frequency unknown: increased body temperature (see section "Special precautions").

Investigations

Frequency unknown: increased blood creatine phosphokinase levels.

Reporting of adverse reactions.

Reporting suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

Keep out of reach of children.

Store at a temperature not exceeding 25 °C, protected from light.

Packaging.

2 ml in ampoules, 6 ampoules in a blister pack, 1 (6×1) or 5 (6×5) blister packs in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

BROS LTD/BROS LTD.

Manufacturer's address and location of operations.

Augis & Galinis 15, Nea Kifisia (Attiki) 14564, Greece.