SULPIRIDE ROSEMONT 200 MG / 5ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Sulpiride Rosemont 200mg/5ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 200 milligrams Sulpiride

Excipient(s) with known effect:

Each 5ml of oral solution contains 3073.5 mg liquid maltitol (E965).

Each 5ml of oral solution contains 6 mg methyl hydroxybenzoa­te (E218)

Each 5ml of oral solution contains 1.5 mg propyl hydroxybenzoa­te (E216)

Each 5ml of oral solution contains 109 mg propylene glycol (E1520)

Each 5ml of oral solution contains 0.19 mg glycerine

Each 5ml of oral solution contains 0.002 mg benzyl alcohol

For the full list of excipients, see section 6.1.

A colourless to slightly yellow oral solution.

4.1 Therapeutic indications

Sulpiride is indicated in acute and chronic schizophrenia.

4.2 Posology and method of administration

Posology

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.

Paediatric population

Clinical experience in children under 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.

Method of administration

For oral administration only.

4.3 Contraindications

Phaeochromocytoma. Acute porphyria.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

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 (see section 4.8 Undesirable effects)

Association with levodopa or antiparkinsonian drugs (including ropinirole) (See

4.5 Interactions with other medicinal products and other forms of interaction)

Bone marrow suppression

4.4 Special warnings and precautions for use

Warnings:

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, principally akathisia have been reported in a small number of cases, a reduction in dosage of sulpiride or initiation of antiparkinsonian medication may be necessary.

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. In such an event, or in the event of hyperthermia of undiagnosed origin, all antipsychotic drugs, including sulpiride, should be discontinued.

Elderly patients are more susceptible to postural hypotension, sedation and extrapyramidal effects.

In patients with aggressive behaviour or agitation with impulsiveness, sulpiride could be given with a sedative.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of antipsychotic drugs. Recurrence of psychotic symptoms may also occur, and the emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has 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 Oral Solution is not licensed for the treatment of dementia-related behavioural disturbances.

Venous thromboembolism

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.

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

Breast cancer

Sulpiride may increase prolactin levels. Therefore, caution should be exercised and patients with a history or a family history of breast cancer should be closely monitored during sulpiride therapy.

Precautions:

In elderly patients, as with other neuroleptics, sulpiride should be used with particular caution (see section 4.2).

In children, efficacy and safety of sulpiride have not been thoroughly investigated. Therefore, caution should be exercised when prescribing to children (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.

Neuroleptics may lower the epileptogenic threshold. Cases of convulsions, sometimes in patients with no previous history, have been reported with sulpiride. 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.

In patients requiring sulpiride who are receiving anti-convulsant therapy, the dose of the anti-convulsant should not be changed.

Cases of convulsions, sometimes in patients with no previous history, have been reported.

Sulpiride has an anticholinergic effect and, therefore, should be used with caution in patients with a history of glaucoma, ileus, congenital digestive stenosis, urine retention or hyperplasia of the prostate. As with all drugs for which the kidney is the major elimination pathway, the dosage should be reduced and titrated in small steps in cases of renal insufficiency.

Prolongation of the QT interval

Sulpiride may induce a prolongation of the QT interval (see section 4.8). 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).

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.

Avoid concomitant treatment with other neuroleptics (see section 4.5).

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 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 4.5 Interactions with other medicaments and other forms of interaction).

Sulpiride should be used with caution in patients with a history of jaundice or with hepatic impairment as it may precipitate coma.

Sulpiride should be used with caution in patients with hypertension, severe respiratory disease and myasthenia gravis.

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 Oral Solution. Unexplained infections or fever may be evidence of blood dyscrasia (see section 4.8) and requires immediate haematological investigation.

Excipient Warnings

The product contains liquid maltitol (E965). Patients with rare hereditary problems of fructose intolerance should not take this medicine. May have a mild laxative effect. Calorific value 2.3kcal/g maltitol.

This product also contains parahydroxyben­zoates (E216 & E218) (preservatives) which may cause allergic reactions (possibly delayed).

This product contains 109mg propylene glycol (E1520) in each 5ml dose. This product contains 654mg propylene glycol in each 30ml dose.

This product contains 0.19mg glycerine in each 5ml dose.

This product contains 0.002mg benzyl alcohol in each 5ml dose. Benzyl alcohol may cause allergic reactions. High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because of the risk of accumulation and toxicity (metabolic acidosis).

4.5 Interaction with other medicinal products and other forms of interaction

Associations contraindicated:

Levodopa, antiparkinsonian drugs (including ropinirole): reciprocal antagonism of effects between levodopa or antiparkinsonian drugs (including ropinirole) and neuroleptics.

Associations not recommended:

Alcohol: Enhances the sedative effect of neuroleptics. Avoid the consumption of alcoholic beverages and drugs containing alcohol.

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, coadministration should be undertaken with caution and ECG monitoring should be considered (see section 4.4).

Dopaminergics: Antagonism of the effects of dopaminergic agents such as amantidine, 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 the deterioration in Parkinsonism and mental state (See section 4.4).

Combination with the following medications could induce torsade de pointes or prolong the QT interval:

– 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 such as pimozide, haloperidol; methadone, imipramine antidepressants; lithium, cisapride, thioridazine, IV erythromycin, halofantrine, pentamidine.

Associations to be taken into account:

Anaesthetics: The hypotensive effect of anaesthetics may be enhanced by concomitant use.

Analgesics: Enhanced sedative and hypotensive effect with opioid analgesics

Antidepressants: Possibility of extrapyramidal symptoms, including Parkinson-like symptoms or dystonia, in patients taking sulpiride and fluoxetine concurrently. Possibly increased risk of ventricular arrhythmias with tricyclic antidepressants.

Antiepileptics: The convulsive threshold may be lowered by sulpiride.

Unnecessary polypharmacy should be avoided. As with other psychotropic compounds, sulpiride may increase the effect of antihypertensives and CNS depressantsor stimulants such as sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytics, clonidine and derivatives.

The bioavailability of sulpiride is reduced by concomitant administration with sucralfate and antacids, therefore, sulpiride should be taken two hours before these drugs.

Also concurrent use with lithium may cause extrapyramidal symptoms to develop. Discontinuation of both drugs is recommended at first signs of neurotoxicity.

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:

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.

In humans, very limited clinical data on exposed pregnancies are available. If sulpiride is used during pregnancy, appropriate monitoring of the neonate should be considered in view of sulpiride safety profile.

The use of sulpiride in the third trimester of pregnancy may result in extrapyramidal effects, lethargy and hypotonia in the neonate.

Neonates exposed to antipsychotics (including Sulpiride) 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.

Breastfeeding:

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

The following CIOMS frequency rating is used, when applicable:

Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Blood and lymphatic system disorders (see section 4.4)

Uncommon: leukopenia

Not known: neutropenia, agranulocytosis, haemolytic anaemia, thrombocytopenic purpura

Immune system disorders

Not known: anaphylactic reactions; urticaria, dyspnoea, hypotension and anaphylactic shock

Endocrine disorders

Common: hyperprolactinaemia

Eye disorders

Not known: blurred vision, corneal and lens opacities, deposition of pigment in the eyes

Psychiatric disorders

Common: insomnia

Not known: confusion, depression, agitation

Nervous system disorders

Common: sedation or drowsiness, extrapyramidal disorder (these symptoms are generally reversible upon administration of antiparkinsonian medication),

Parkinsonism, tremor, akathisia

Uncommon: hypertonia, dyskinesia, dystonia

Rare: oculogyric crisis

Not known: neuroleptic malignant syndrome, hypokinesia, tardive dyskinesia (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), convulsion

Metabolism and nutrition disorders

Not known: hyponatraemia, syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyperglycaemia, hypothermia, hyperthermia

Cardiac disorders

Rare: ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia Not known: electrocardiogram QT prolonged, cardiac arrest, torsade de pointes, sudden death (see section 4.4).

Vascular disorders

Uncommon: orthostatic hypotension

Not known: venous embolism, pulmonary embolism, deep vein thrombosis (see section 4.4)

Respiratory, thoracic and mediastinal disorders

Not known: pneumonia aspiration (mainly in association with other CNS depressants), nasal congestion

Gastrointestinal disorders

Common: constipation

Uncommon: salivary hypersecretion

Not known: dry mouth

Hepatobiliary disorders

Common: hepatic enzyme increased

Not known: jaundice, hepatitis

Skin and subcutaneous tissue disorders

Common: maculo-papular rash

Not known: contact sensitivity, exfoliative dermatitis, pigmentation of the skin, photosensitivity and skin rashes

Musculoskeletal and connective tissue disorders

Not known: torticollis, trismus

Pregnancy, puerperium and perinatal conditions

Not known: extrapyramidal symptoms, drug withdrawal syndrome neonatal (see section 4.6)

Renal and urinary disorders

Not known: difficulties with micturition

Reproductive system and breast disorders

Common: breast pain, galactorrhoea

Uncommon: breast enlargement, amenorrhoea, orgasm abnormal, erectile dysfunction.

Not known: gynaecomastia, ejaculatory dysfunction

General disorders and administration site conditions

Common: weight gain

Reporting of suspected adverse reactions:

Reporting 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Experience with sulpiride in overdosage is limited.

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 (see section 4.8 Undesirable Effects); 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.

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.

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

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics; Benzamides

ATC code: N05AL01

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 invitro, 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 halflife 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.

6.1 List of excipients

Methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216), propylene glycol (E1520), citric acid monohydrate (E330), liquid maltitol (E965), lemon flavour (containing propylene glycol (E1520), glycerine, and benzyl alcohol), aniseed flavour (containing propylene glycol (E1520)) and purified water.

6.2. Incompatibilities

None known

6.3.

36 months – unopened

3 months – opened

6.4.

Do not store above 25°C.

6.5

Bottle:

Closure:

150ml amber (Type III) glass.

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

6.6 Special precautions for disposal

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

Any unused medicinal product or waste material should be disposed of in accordance with local requirements

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds, LS11 9XE

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00427/0129

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

Date of first authorisation: 08 August 2001

Date of latest renewal: 07 April 2009

10