Sulpor 200mg / 5ml Oral Solution.

1. Name Of The Medicinal Product

Sulpiride 200mg/5ml Oral Solution.

Sulpor

2. Qualitative And Quantitative Composition

Sulpiride 200mg/5ml.

3. Pharmaceutical Form

A colourless to slightly yellow oral solution.

4. Clinical Particulars

4.1 Therapeutic Indications

Acute and chronic schizophrenia.

4.2 Posology And Method Of Administration

For oral administration only.

Adults:

A starting dose of 400mg to 800mg daily, given in two divided doses (morning and early evening) is recommended.

Predominantly positive symptoms (formal thought disorder, hallucinations, delusions, incongruity of affect) respond to higher doses, and a starting dose of at least 400mg twice daily is recommended, increasing if necessary up to a suggested maximum of 1200mg twice daily. Increasing the dose beyond this level has not been shown to produce further improvement. Predominantly negative symptoms (flattening of affect, poverty of speech, anergia, apathy), as well as depression, respond to doses below 800mg daily; therefore, a starting dose of 400mg twice daily is recommended. Reducing this dose towards 200mg twice daily will normally increase the alerting effect of sulpiride.

Patients with mixed positive and negative symptoms, with neither predominating, will normally respond to dosage of 400-600mg twice daily.

Children:

Clinical experience in children under the age of 14 years of age is insufficient to permit specific recommendations.

Elderly:

The same dose ranges may be required in the elderly, but should be reduced if there is evidence of renal impairment.

4.3 Contraindications

Phaeochromocytoma. Acute porphyria. Hypersensitivity to any of the ingredients in this product. Severe renal, haematological or hepatic disease. Alcoholic intoxication and other disorders which depress CNS function.

Concomitant prolactin-dependant tumours e.g. pituitary gland prolactinomas and breast cancer

Association with levodopa (See 4.5 Interactions with other medicinal products and other forms of interaction)

4.4 Special Warnings And Precautions For Use

Increased motor agitation has been reported at high dosage in a small number of patients: in aggressive, agitated or excited phases of the disease process, low doses of sulpiride may aggravate symptoms. Care should be exercised where hypomania is present.

If extrapyramidal reactions occur, a reduction in dosage of sulpiride or initiation of anti-parkinsonian medication may be necessary.

As with all neuroleptic drugs, the presence of unexplained hyperthermia could indicate the neuroleptic malignant syndrome (NMS). In this event sulpiride and any associated neuroleptic treatment should be discontinued until the origin of the fever has been determined.

Although sulpiride only induces slight EEG modifications, caution is advised in prescribing it for patients with unstable epilepsy. Patients requiring sulpiride who are receiving anti-convulsant therapy should continue unchanged on the latter medication. Cases of convulsions, sometimes in patients with no previous history, have been reported.

Sulpiride has no significant anticholinergic or cardiovascular activity.

As with all drugs for which the kidney is the major elimination pathway, the usual precautions should be taken in cases of renal failure.

Patients should be warned against taking alcohol with sulpiride as reaction capacity may be impaired.

Abrupt cessation of treatment in some patients may produce a withdrawal response.

Elderly patients are more susceptible to postural hypotension, sedation and extrapyramidal effects. As with other neuroleptics, sulpiride should be used with particular caution (see section 4.2).

When neuroleptic treatment is absolutely necessary in a patient with Parkinson's disease, sulpiride can be used, although caution is in order.

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.

Prolongation of the QT interval

Sulpiride may induce a prolongation of the QT interval. This effect, known to potentiate the risk of serious ventricular arrhythmias such as torsade de pointes is enhanced by the pre-existence of bradycardia or cardiovascular disease, hypokalaemia, congenital or acquired long QT interval, concomitant neuroleptic treatment, or a family history of QT prolongation (See section 4.5).

An approximately 3-fold increased risk of cerebrovascular adverse events have been seen in randomised placebo controlled clinical trials in the dementia population with some atypical antipsychotics. The mechanism for this increased risk cannot be excluded for other antipsychotics or other patient populations. Sulpiride should be used with caution in patients with risk factors for stroke.

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 Oral Solution is not licensed for the treatment of dementia-related behavioural disturbances.

Excipient Warnings

The product contains liquid maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

This product also contains parahydroxybenzoates (preservatives) which may cause allergic reactions (possibly delayed).

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

While no drug interactions are known, unnecessary polypharmacy should be avoided. As with other psychotropic compounds, sulpiride may increase the effect of antihypertensives and CNS depressants or stimulants.

Sulpiride results in reciprocal antagonism of effects between levodopa and neuroleptics.

The bioavailability of sulpiride is reduced by concomitant administration with sucralfate and antacids and should not, therefore, be taken at the same time.

Also concurrent use with lithium may cause extrapyramidal symptoms to develop.

Sulpiride may reduce the effectiveness of ropinorole.

Combination with the following medications which could induce torsade de pointes:

- Bradycardia-inducing medications such as beta-blockers, bradycardia-inducing calcium channel blockers such as diltiazem and verapamil, clonidine; digitalics.

- Medications which induce hypokalaemia: Hypokalaemic diuretics, stimulant laxatives, IV amphotericin B, glucocorticoids, tetracosactides.

- Class Ia antiarrhythmic agents such as quinidine, disopyramide.

- Class III antiarrhythmic agents such as amiodarone, sotalol.

- Other medications such as pimozide, haloperidol; imipramine antidepressants; cisapride, thioridazine, IV erythromycin, pentamidine.

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).

4.6 Pregnancy And Lactation

Despite the negative results of teratogenicity studies in animals and the lack of teratogenic effects during widespread clinical use in other countries, sulpiride should not be considered an exception to the general principle of avoiding drug treatment in pregnancy, particularly during the first 16 weeks, with potential benefits being weighed against possible hazards.

Sulpiride has been found in low concentrations in breast milk. It is, therefore, recommended that the use of sulpiride be avoided in patients who are breast feeding.

4.7 Effects On Ability To Drive And Use Machines

Patients should be advised not to drive or operate machinery if they experience symptoms of slowing of reaction time, drowsiness or loss of concentration.

4.8 Undesirable Effects

Sulpiride is very well tolerated and usually only minor side-effects occur, if at all, at the recommended doses.

Neuroleptic malignant syndrome. As with other neuroleptics, rare cases of neuroleptic malignant syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated CPK levels, have been reported. In such an event, all antipsychotic drugs, including Sulpor, Sulpiride 200mg/5ml Oral Solution, should be discontinued (section 4.4 Special warnings and precautions for use).

Very rare cases of convulsions have been reported, in particular in epileptic patients (see section 4.4 Special warnings and precautions for use).

Extrapyramidal symptoms and related disorders:

-parkinsonism and related symptoms (tremor, hypertonia, hypokinesia, hypersalivation)

-acute dyskinesia and dystonia (spasm torticollis, oculogyric crisis, trismus)

-akinesia.

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.

Sedation or drowsiness. Insomnia has been reported.

Hepatic reactions including jaundice and hepatitis have been reported.

As is usual with neuroleptics and psychotic drugs, sulpiride raises serum prolactin levels, which may be associated with galactorrhoea, oligomenorrhoea and amenorrhoea, and less frequently with gynaecomastia. Sexual function may also be increased or decreased.

Postural hypotension, body weight gain (potentially significant in very rare cases) and very rare cases of hypersensitivity reactions such as skin reactions have been reported.

A mild laxative effect or diarrhoea may be caused by the liquid maltitol in the formulation.

Very rare cases of QT prolongation and very rare cases of torsade de pointes have been reported.

Ventricular arrhythmias such as VF, VT (rare), sudden unexplained death, cardiac arrest are class effects of neuroleptics.

Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs – Frequency unknown

4.9 Overdose

The range of single toxic doses is 1 to 16g but no death has occurred even at the 16g dose.

The clinical manifestations of poisoning vary depending upon the size of the dose taken. After single doses of 1 to 3g restlessness and clouding of consciousness have been reported and (rarely) extrapyramidal symptoms.

Doses of 3 to 7g may produce a degree of agitation, confusion and extrapyramidal symptoms; more than 7g can cause, in addition, coma and low blood pressure.

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. There are no specific complications from overdose. In particular no haematological or hepatic toxicity has been reported.

Overdose may be treated with alkaline osmotic diuresis and, if necessary, anti-parkinsonian drugs. Coma needs appropriate nursing. Emetic drugs are unlikely to be effective in sulpiride overdosage.

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 administered.

5. Pharmacological Properties

5.1 Pharmacodynamic Properties

One of the characteristics of sulpiride is its bimodal activity, as it has both antidepressant and neuroleptic 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 sedation and lack of effect characteristically associated with classical neuroleptics of the phenothiazine or butyrophenone type are not features of sulpiride therapy.

Sulpiride is a member of the group of substituted benzamides, which are structurally distinct from the phenothiazines, butyrophenones and thioxanthenes. Current evidence suggests that the actions of sulpiride hint at an important distinction between different types of dopamine receptors or receptor mechanisms in the brain.

Behaviourally and biochemically, sulpiride shares with these classical neuroleptics a number of properties indicative of cerebral dopamine receptor antagonism. Essential and intriguing differences include lack of catalepsy at doses active in other behavioural tests, lack of effect in the dopamine sensitive adenylate cyclase systems, lack of effect upon noradrenaline or 5HT turnover, negligible anticholinesterase activity, no effect on muscarinic or GABA receptor binding, and a radical difference in the binding of tritiated sulpiride to striatal preparations in-vitro, compared to ³H-spiperone and ³H-haloperidol. These findings indicate a major differentiation between sulpiride and classical neuroleptics which lack such specificity.

5.2 Pharmacokinetic Properties

Peak sulpiride serum levels are reached 3-6 hours after an oral dose. The plasma half-life in man is approximately 8 hours. Approximately 40% sulpiride is bound to plasma proteins. 95% 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 but not all strains of rats and mice studied. The significance of these findings 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

Methyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol, citric acid monohydrate, liquid maltitol, lemon flavour, aniseed flavour and purified water.

6.2 Incompatibilities

None known.

6.3 Shelf Life

36 months – unopened

3 months - opened

6.4 Special Precautions For Storage

Do not store above 25°C.

6.5 Nature And Contents Of Container

Bottle: 150ml amber (Type III) glass.

Closure: a) Aluminium, EPE wadded, roll-on pilfer-proof screw cap.

b) HDPE, EPE wadded, tamper evident screw cap.

c) HDPE, EPE wadded, tamper evident, child resistant closure.

6.6 Special Precautions For Disposal And Other Handling

The date of opening should be entered on the label next to the “use within 3 months of opening” statement.

Administrative Data

7. Marketing Authorisation Holder

Rosemont Pharmaceuticals Ltd, Rosemont House, Yorkdale Industrial Park, Braithwaite Street, Leeds, LS11 9XE, UK.

8. Marketing Authorisation Number(S)

PL 00427/0129

9. Date Of First Authorisation/Renewal Of The Authorisation

08.08.01/07.04.09

10. Date Of Revision Of The Text

22/01/2010