Sulpiride 400mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Sulpiride 400mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Sulpiride 400mg.
For excipients, see 6.1
3 PHARMACEUTICAL FORM
Tablet.
Sulpiride Tablets 400mg are white, oval, film coated tablets marked S400 and breakline on one face and CP on the reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
The treatment of acute and chronic schizophrenia.
4.2 Posology and method of administration
Adults: The initial dose depends on the nature of the symptoms.
In patients with predominantly negative symptoms the usual starting dose is 400mg twice daily. This can be reduced to 200mg twice daily as a response occurs, increasing the alerting effect of sulpiride which occurs at lower doses.
In patients with predominantly positive symptoms the usual starting dose is 400mg twice daily increasing if necessary to a suggested maximum of 1200 mg twice daily.
In patients with positive and negative symptoms, with neither predominating, a dose of 400mg-600mg twice daily is recommended.
Elderly: Initially one quarter to one half of the adult dose.
Children: Not recommended for children under 14 years of age.
Renal impairment: The dosage should be reduced or the dosage interval increased.
4.3 Contraindications
• Sensitivity to sulpiride or any of the ingredients of sulpiride tablets
• Phaeochromocytoma
• Acute porphyria
• Comatose state or CNS depression
• Bone-marrow suppression
• Prolactin dependant tumours e.g. pituitary gland prolactinomas and breast cancer
• Concomitant treatment with levodopa (see section 4.5)
4.4 Special warnings and precautions for use
Increased motor agitation has been reported at high dosage in a small number of patients given sulpiride. Sulpiride may aggravate symptoms in aggressive, agitated or excited phases of the disease process. Care should be exercised where mania or hypomania is present.
In patients with aggressive behaviour or agitation with impulsiveness, sulpiride could be given with a sedative.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with Sulpiride and preventive measures undertaken.
If extrapyramidal reactions occur, a reduction in dosage of sulpiride or initiation of anti-parkinsonian medication may be necessary.
Sulpiride should be given with caution to patients suffering from extrapyramidal disturbances as these may be aggravated by sulpiride. Patients on concomitant dopaminergics should be monitored for deterioration in parkinsonism and mental state (see section 4.5).
Avoid concomitant treatment with other neuroleptics (see section 4.5).
As with other neuroleptics, neuroleptic malignant syndrome, a potentially fatal complication, which is characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK levels, has been reported (see section 4.8). In such an event, or in the event of hyperthermia of undiagnosed origin, all antipsychotic drugs, including Sulpiride, should be discontinued.
Sulpiride should be given with caution to elderly patients as they are more susceptible to postural hypotension, sedation and extrapyramidal effects. The initial dosage should be reduced (see section 4.2)
Sulpiride has no significant anticholinergic effect.
In patients requiring sulpiride who are receiving anti-convulsant therapy, the dose of the anti-convulsant should not be changed.
Neuroleptics may lower the epileptogenic threshold. Cases of convulsions, sometimes in patients with no previous history, have been reported with sulpiride (see section 4.8). Caution is advised in prescribing it for patients with unstable epilepsy, and patients with a history of epilepsy should be closely monitored during therapy with sulpiride.
Sulpiride should be given with caution to patients with renal disease and the dosage or frequency of administration should be reduced (see section 4.2).
Sulpiride should be used with caution in patients with a history of jaundice or with hepatic impairment, as it may precipitate coma.
Prolongation of the QT interval:
Sulpiride induces a prolongation of the QT interval (see section 4.8). This effect is known to potentiate the risk of serious ventricular arrhythmias such as torsade de pointes.
Before any administration, and if possible according to the patient's clinical status, it is recommended to monitor factors which could favour the occurrence of this rhythm disorder, for example:
- Bradycardia less than 55 bpm
- Electrolyte imbalance in particular hypokalaemia
- Congenital prolongation of the QT interval
- On-going treatment with a medication likely to produce pronounced bradycardia (< 55 bpm), hypokalaemia, decreased intracardiac conduction, or prolongation of the QTc interval (see section 4.5)
Sulpiride should be prescribed with caution in patients presenting with these factors and patients with cardiovascular disorders which may predispose to prolongation of the QT interval.
Sulpiride should be used with caution in patients with hypertension, severe respiratory disease including asthma, myasthenia gravis and prostatic hypertrophy.
Stroke:
In randomised clinical trials versus placebo performed in a population of elderly patients with dementia and treated with certain atypical antipsychotic drugs, a 3-fold increase of the risk of cerebrovascular events has been observed. The mechanism of such risk increase is not known. An increase in the risk with other antipsychotic drugs or other populations of patients cannot be excluded. Sulpiride should be used with caution in patients with stroke risk factors.
Sulpiride should be used with caution in patients with a personal or family history of angle-closure glaucoma.
As photosensitisation may occur with higher doses, avoidance of undue exposure to direct sunlight is recommended.
Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including sulpiride. Unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8) and requires immediate haematological investigation.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Withdrawal: Stopping treatment with an antipsychotic abruptly may produce withdrawal symptoms, the most common include nausea, vomiting, diarrhoea, rhinorrhoea, myalgias, insomnia and anxiety. Patients may also experience sweating, vertigo and tremor. Withdrawal symptoms generally begin within 1 to 4 days of the last dose. The symptoms may be more severe and frequent when antimuscarinincs are stopped simultaneously. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) have been reported. Therefore, gradual withdrawal is advisable.
Increased Mortality in Elderly people with Dementia Data from two large observational studies showed that elderly people with dementia who are treated with antipsychotics are at a small increased risk of death compared with those who are not treated. There are insufficient data to give a firm estimate of the precise magnitude of the risk and the cause of the increased risk is not known.
Sulpiride is not licensed for the treatment of dementia-related behavioural disturbances.
4.5 Interaction with other medicinal products and other forms of interaction
Alcohol: Enhances the sedative effects of neuroleptics. Avoid the consumption of alcoholic beverages and drugs containing alcohol.
Anaesthetics: The hypotensive effect of anaesthetics may be enhanced by concomitant use.
Analgesics: enhanced sedative and hypotensive effect with opioid analgesics.
Antacids: Administration of sucralfate or antacids containing aluminium and magnesium hydroxides may reduce the bioavailability of sulpiride, which should be administered at least 2 hours before and not with or after sucralfate or these antacids.
Combination with the following medications could induce torsades de pointes or prolong the QT interval (see section 4.4):
- Bradycardia-inducing medications such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine; digitalis
- Medications which induce electrolyte imbalance, in particular those causing hypokalaemia: hypokalaemic diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, tetracosactides.
Electrolyte imbalance should be corrected
- Class Ia antiarrhythmic agents such as quinidine, disopyramide.
- Class III antiarrhythmic agents such as amiodarone, sotalol.
- Other medications known to prolong the QT interval, examples include certain antibiotics and antifungals (such as quinupristin, dalfopristin, pentamide and IV erythromycin, tricyclic antidepressants (such as amitriptyline), other neuroleptics (such as haloperidol, pimozide, thioridazine), certain antihistamines (such as terfenadine), certain antimalarials (such as mefloquine, quinine, halofantrine), methadone, imipramine antidepressants, lithium, cisapride. This list is not comprehensive.
Use with concomitant QT prolonging drugs and with drugs causing electrolyte imbalance is not recommended. If the benefit is considered to outweigh the risk in the individual patient, co-administration should be undertaken with caution and ECG monitoring should be considered (see section 4.4).
Antidepressants: possibility of extrapyramidal symptoms, including parkinson-like symptoms or dystonia, in patients taking sulpiride and fluoxetine concurrently.
Antidiabetic drugs: The dose of oral antidiabetic drugs or insulin may need to be increased in patients taking antipsychotics.
Antiepileptics: The convulsive threshold may be lowered by sulpiride.
Antihypertensives: As with other psychotropic compounds, sulpiride may enhance the hypotensive effect of antihypertensives.
Anxiolytics: increased effect of CNS depressants including hypnotics and anxiolytics.
Dopaminergics: Antagonism of the effects of dopaminergic agents such as amantadine, bromocriptine, cabergoline and lisuride. Pramipexole and ropinirole should be avoided. Concomitant use of dopaminergic agents may also lead to exacerbation of psychotic symptoms. The patient should be monitored for deterioration in parkinsonism and mental state (refer to section 4.4). Sulpiride results in reciprocal antagonism of effects between levodopa and neuroleptics.
Lithium: increased risk of extrapyramidal effects.
Metoclopramide: concomitant use may increase the risk of antipsychotic-induced extrapyramidal effects.
Sympathomimetics: The pressor effects of sympathomimetics may be antagonised when taken concomitantly with sulpiride, resulting in severe hypotension.
4.6 Fertility, pregnancy and lactation
Pregnancy
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/fetal development and/or postnatal development.
In humans, very limited clinical data on exposed pregnancies are available. The use of sulpiride is not recommended during pregnancy, particularly during the first trimester, with potential benefits being weighed against potential risks.
If sulpiride is used during pregnancy, appropriate monitoring of the neonate should be considered in view of sulpiride safety profile.
Neonates exposed to antipsychotics (including Sulpiride 400mg Film-Coated Tablets) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast-feeding
Sulpiride is excreted into breast milk. Breast-feeding is not recommended during treatment.
Fertility
A decrease in fertility linked to the pharmacological effects of the drug (prolactin mediated effect) was observed in treated animals.
4.7 Effects on ability to drive and use machines
Sulpiride is less prone to produce drowsiness than other conventional neuroleptics. Patients receiving high doses of sulpiride should be warned of the hazards of driving or operating machinery until the drug has been shown not to interfere with their physical or mental ability.
4.8 Undesirable effects
Blood and lymphatic system disorders: Agranulocytosis, haemolytic anaemia, thrombocytopenic purpura, leucopenia and eosinophilia.
Immune system disorders: contact sensitivity, exfoliative dermatitis and urticaria.
Endocrine disorders: Hyperprolactinaemia, hyponatraemia secondary to inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders: hyperglycaemia, hypothermia, hyperthermia, weight gain and hyperlipidaemia.
Psychiatric disorders: delirium/confusion, catatonia, depression, drowsiness and/or sedation, lassitude and insomnia. Sleep disturbances, nightmares, overstimulation and agitation may occur.
Nervous system disorders
Extrapyramidal symptoms and related disorders:
- parkinsonism and related symptoms: tremor, hypertonia, hypokinesia, hypersalivation
-acute dyskinesia and dystonia (spasm torticollis, oculogyric crisis, trismus) -akathisia
These symptoms are generally reversible upon administration of antiparkinsonian medication.
Tardive dyskinesia (characterised by rhythmic, involuntary movements primarily of the tongue and/or the face) have been reported, as with all neuroleptics, after a neuroleptic administration of more than 3 months. Antiparkinsonian medication is ineffective or may induce aggravation of the symptoms.
Convulsions have been reported, in particular in patients with epilepsy. (see section 4.4).
Eye disorders: corneal and lens opacities, deposition of pigment in the eyes and blurred vision.
Cardiac disorders: hypertension, electrocardiographic (ECG) changes, QT prolongation, ventricular fibrillation and tachycardia (rare), cardiac arrest, Torsades de pointes and sudden unexplained death.
Vascular disorders: hypotension (in high doses), orthostatic hypotension. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs-Frequency unknown.
Respiratory, thoracic and mediastinal disorders: Nasal congestion.
Gastrointestinal disorders: dry mouth and constipation.
Hepatobiliary disorders: Jaundice and elevated hepatic enzymes.
Skin and subcutaneous tissue disorders: pigmentation of the skin, photosensitivity and skin rashes.
Renal and urinary disorders: difficulties with micturition.
Pregnancy, puerperium and perinatal conditions: Drug withdrawal syndrome neonatal (see section 4.6). Frequency unknown.
Reproductive system and breast disorders: Therapeutic doses of antipsychotics raise serum prolactic levels. Long-term use may be associated with galactorrhoea, amenorrhoea, infertility, gynaecomastia, breast enlargement and breast pain.
Priapism, ejaculatory dysfunction, impotence, increase and decreased libido.
General disorders and administration site conditions: Neuroleptic malignant syndrome (see section 4.4) which is a potentially fatal reaction. In such an even all antipsychotics drugs, including sulpiride, should be discontinued.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Experience with sulpiride in overdosage is limited.
The range of single toxic doses is 1 to 16g but no deaths have occurred even at a dose of 16g.
Symptoms
The clinical manifestations of poisoning vary depending upon the size of the dose taken. After single doses of 1g to 3g restlessness and clouding of consciousness have been reported and (rarely) extrapyramidal symptoms. Doses of 3g to 7g may produce a degree of agitation, confusion and extrapyramidal symptoms; more than 7g can cause, in addition, coma and low blood pressure. Other possible symptoms of overdose include: hypothermia, convulsions and arrhythmias.
The duration of intoxication is generally short, the symptoms disappearing within a few hours. Comas which have occurred after large doses have lasted up to four days.
No haematological or hepatic toxicity has been reported.
Treatment
Sulpiride is partly removed by haemodialysis.
There is no specific antidote to sulpiride. Treatment is only symptomatic. Appropriate supportive measures should therefore be instituted, close supervision of vital functions and cardiac monitoring (risk of QT interval prolongation and subsequent ventricular arrhythmias) is recommended until the patient recovers.
If severe extrapyramidal symptoms occur anticholinergics should be administrated.
Overdose may be treated with alkaline osmotic diuresis and, if necessary, antiparkinsonian drugs. Emetic drugs are unlikely to be effective. Coma needs appropriate nursing.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Sulpiride is a member of the group of substituted benzamides, which are structurally distinct from the phenothiazines, butyrophenones and thioxanthenes.
Behaviourally and biochemically sulpiride shares with classical neuroleptics a number of properties indicative of cerebral dopamine receptor antagonism. Differences include lack of effect upon noradrenaline or 5HT turnover, negligible anticholinesterase activity, no effect on muscarinic or GABA receptor binding. These findings indicate a major differentiation between sulpiride and classical neuroleptics which lack such specificity.
One of the characteristics of sulpiride is its bimodal activity, as it has both antidepressant and antipsychotic properties. Schizophrenia characterised by a lack of social contact can benefit strikingly.
Mood elevation is observed after a few days treatment, followed by disappearance of the florid schizophrenic symptoms. The sedative, anti-muscarinic, alpha-blocking and extrapyramidal effects of sulpiride are less pronounced than those characteristically associated with classical neuroleptics of the phenothiazine type.
5.2 Pharmacokinetic properties
The bioavailability of the oral form ranges from 25-40%. Peak sulpiride serum levels are reached 2-6 hours after an oral dose. The plasma half life in man is 6-8 hours.
Sulpiride is less than 40% bound to plasma proteins. Sulpiride crosses the blood-brain barrier. Ninety five percent of the compound is excreted in the urine and faeces as unchanged sulpiride.
5.3 Preclinical safety data
In long term animal studies with neuroleptic drugs including sulpiride, an increased incidence of various endocrine tumours (some of which have occasionally been malignant) has been seen in some strains of rats and mice
studied. The significance of these to man is not known; there is no current evidence of any association between neuroleptic use and tumour risk in man. However, when prescribing neuroleptics to patients with existing mammary neoplasia or a history of this disease, possible risks should be weighed against benefits of therapy.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose Povidone K30 Microcrystalline cellulose Sodium starch glycollate Magnesium stearate
6.2 Incompatibilities
None Known
6.3 Shelf life
3 years
6.4 Special precautions for storage
Do not store above 25°C
6.5 Nature and contents of container
Multiples of 10 or 14 tablets in strips of PVC/Aluminium foil.
Multiples of 10 or 14 tablets in polypropylene/polyethylene containers with tamper evident closures.
6.6 Special precautions for disposal
None
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0192
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
1/01/2008
10 DATE OF REVISION OF THE TEXT
20/02/2014