| 1. NAME OF THE MEDICINAL PRODUCT |
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Dolmatil Tablets 200mg
Dolmatil Tablets 400mg
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| 2. QUALITATIVE AND QUANTITATIVE COMPOSITION |
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Dolmatil Tablets 200mg: active ingredient is sulpiride 200mg.
Dolmatil Tablets 400mg: active ingredient is sulpiride 400mg
Sulpiride is a benzamide derivative.
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| 3. PHARMACEUTICAL FORM |
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Dolmatil Tablets 200mg: Plain white round tablet with a transverse breakline on one side and D200 on the other.
Dolmatil Tablets 400mg: White film coated stick shaped tablets with break bar engraved SLP 400 on one side.
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| 4. CLINICAL PARTICULARS |
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4.1 Therapeutic indications
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Acute and chronic schizophrenia.
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4.2 Posology and method of administration
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Adults
A starting dose of 400mg to 800mg daily, given as one or two tablets twice daily (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 Dolmatil.
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 14 years of age is insufficient to permit specific recommendations.
Elderly
The same dose ranges are applicable in the elderly, but the dose should be reduced if there
is evidence of renal impairment.
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4.3 Contraindications
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Phaeochromocytoma and acute porphyria.
Hypersensitivity to the active ingredient or to other ingredients of the drug.
Concomitant prolactin-dependent tumours e.g. pituitary gland prolactinomas and breast cancer (See 4.8 Undesirable effects).
Association with levodopa (See 4.5 Interactions with other medicinal products and other forms of interaction).
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4.4 Special warnings and precautions for use
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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 Dolmatil may aggravate symptoms. Care should be exercised where hypomania is present.
Extrapyramidal reactions, principally akathisia have been reported in a small number of cases. If warranted, reduction in dosage or anti-parkinsonian 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, all antipsychotic drugs, including Dolmatil, 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) have been reported. Therefore, gradual withdrawal is advisable.
Precautions:
In elderly patients, as with other neuroleptics, sulpiride should be used with particular caution (see 4.2 Posology and method of administration).
In children, efficacy and safety of sulpiride have not been thoroughly investigated. Therefore, caution should be exercised when prescribing to children (see 4.2 Posology and method of administration).
When neuroleptic treatment is absolutely necessary in a patient with Parkinson's disease, sulpiride can be used, although caution is in order.
Dolmatil induces slight EEG modifications only, and whilst neuroleptics may lower the epileptogenic threshold, this has not been evaluated 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 Dolmatil 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.
Dolmatil has no significant anticholinergic effect. As with all drugs for which the kidney is the major elimination pathway, the dose 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. This effect, known to potentiate the risk of serious ventricular arrhythmias such as torsade de pointes is enhanced by the pre-existence of bradycardia, hypokalaemia, congenital or acquired long QT interval.
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
- bradycardia less than 55 bpm,
- hypokalaemia (which should be corrected),
- 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 § 4.5 Interaction with other medicinal products and other forms of interactions).
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4.5 Interaction with other medicinal products and other forms of interaction
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4.5.1 Associations contra-indicated
Levodopa: reciprocal antagonism of effects between levopoda and neuroleptics.
4.5.2 Associations not recommended.
Alcohol: alcohol enhances the sedative effects of neuroleptics.
Avoid the consumption of alcoholic beverages and drugs containing alcohol.
Combination with the following medications which could induce torsades 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.
Hypokalaemia 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; imipramine antidepressants; cisapride, thioridazine, IV erythromycin, pentamidine.
4.5.3 Associations to be taken into account.
Antihypertensive agents: antihypertensive effect and possibility of enhanced postural hypotension (additive effect).
CNS depressants including narcotics, analgesics, sedative H1 antihistamines, barbiturates, benzodiazepines and other anxiolytics, clonidine and derivatives.
Antacids or sucralfate: The absorption of sulpiride is decreased after co-administration. Therefore, sulpiride should be administered two hours before these drugs.
Lithium increases the risk of extrapyramidal side effects.
Sulpiride may reduce the effectiveness of ropinorole.
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4.6 Pregnancy and lactation
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Pregnancy:
Reproduction studies were performed in mouse, rat and rabbit by oral and subcutaneous route.
In the rat, fertility and reproductive performance were affected with dose related effect from 40mg/kg. This effect reversed after 4 weeks. A delay in delivery was observed at 640mg/kg by oral route and from 80mg/kg by subcutaneous route. These effects are considered to be in relation with the pharmacological activity on prolactin secretion.
In none of the 3 species did the compound show embryotoxic or teratogenic effect at doses of up to 640 mg/kg.
In humans, even though in almost all cases of foetal or neonatal disorders reported in the context of sulpiride during pregnancy alternative explanations can be suggested and seem more likely, the use of sulpride is not recommended during pregnancy because of the limited experience.
Lactation: Sulpiride has been found in the breast milk of treated women. Therefore breast-feeding is not recommended during treatment.
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4.7 Effects on ability to drive and use machines
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Even used as recommended, sulpiride may affect reaction time so that the ability to drive vehicles or operate machinery can be impaired.
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4.8 Undesirable effects
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Cardiovascular disorders:
- Postural hypotension
- Very rare cases of QT prolongation and of torsade de pointes
Endocrine disorders:
-Hyperprolactinaemia
General disorders and administration site conditions:
- As with all neuroleptics, malignant syndrome (see Section 4.4 Special Warnings and Special Precautions for Use) which is a potentially fatal complication
- Weight gain
Hepatobiliary disorders:
- Very rare cases of increase in hepatic enzymes
Nervous system disorders:
- Sedation or drowsiness. Insomnia has been reported.
- 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 rythmic, 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.
- Very rare cases of convulsions have been reported in particular in patients with epilepsy. (see Section 4.4 Special Warnings and Special Precautions for Use)
Reproductive system and breast disorders:
Disorders related to hyperprolactinaemia:
- Galactorrhoea
- Amenorrhoea
- Gynaecomastia
- Breast enlargement and breast pain
- Orgasmic dysfunction and impotence
Skin and subcutaneous tissue disorders:
- Very rare cases of maculo-papular rash
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4.9 Overdose
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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.
In cases of severe extrapyramidal symptoms anticholinergics should be administrated.
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.
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 is recommended until the patient recovers.
Overdose may be treated with alkaline osmotic diuresis and, if necessary, anti-parkinsonian drugs. Coma needs appropriate nursing, and cardiac monitoring is recommended until the patient recovers. Emetic drugs are unlikely to be effective in Dolmatil overdosage.
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| 5. PHARMACOLOGICAL PROPERTIES |
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5.1 Pharmacodynamic properties
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Dolmatil 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 Dolmatil hint at an important distinction between different types of dopamine receptors or receptor mechanisms in the brain.
Behaviourally and biochemically, Dolmatil 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 or 3H-haloperidol. These findings indicate a major differentiation between Dolmatil and classical neuroleptics which lack such specificity.
One of the characteristics of Dolmatil 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 affect characteristically associated with classical neuroleptics of the phenothiazine or butyrophenone type are not features of Dolmatil therapy.
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5.2 Pharmacokinetic properties
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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.
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5.3 Preclinical safety data
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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 an association between neuroleptic use and tumour risk in man.
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| 6. PHARMACEUTICAL PARTICULARS |
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6.1 List of excipients
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Dolmatil Tablets 200mg: Starch, lactose, methylcellulose, magnesium stearate, talc, silica.
Domlatil Tablets 400mg: Lactose, sodium starch glycollate, microcrystalline cellulose, hydroxypropymethyl-cellulose and magnesium stearate
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6.2 Incompatibilities
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6.3 Shelf life
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6.4 Special precautions for storage
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6.5 Nature and contents of container
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Cartons containing 100 tablets in blister strips
Dolmatil Tablets 400mg: strip-wrapped in a moulded bubble blister pack in 200µg PVC, heat sealed with 0.02mm printed laminated aluminium foil. Contains 100 tablets.
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6.6 Instructions for use, handling and disposal
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| 7. MARKETING AUTHORISATION HOLDER |
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Sanofi-Synthelabo Limited
One Onslow Street
Guildford
Surrey
GU1 4YS
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| 8. MARKETING AUTHORISATION NUMBER(S) |
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Dolmatil Tablets 200mg: PL 11723/0339
Dolmatil Tablets 400mg: PL 11723/0340
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| 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION |
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Dolmatil Tablets 200mg:15 October 2002
Dolmatil Tablets 400mg: 15 October 2002
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| 10. DATE OF REVISION OF THE TEXT |
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Dolmatil Tablets 200mg: 14th December 2005
Dolmatil Tablets 400mg: 14th December 2005
Legal Category: POM
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