Dolmatil

The treatment of acute and chronic schizophrenia.

Posology

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 Dolmatile.

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

Elderly

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

Paediatric population

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

Method of administration

For oral use.

Phaeochromocytoma and acute porphyria.

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

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 Dolmatile may aggravate symptoms. Care should be exercised where mania or 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, or in the event of hyperthermia of undiagnosed origin, all antipsychotic drugs, including Dolmatile, should be discontinued.

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

In patients with aggressive behaviour or agitation with impulsiveness, Dolmatile 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.

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.

Dolmatile is not licenced 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 Dolmatile and preventive measures undertaken.

Breast cancer:

Dolmatile 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 Dolmatile therapy.

Precautions:

In elderly patients, as with other neuroleptics, Dolmatile should be used with particular caution.

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

When neuroleptic treatment is absolutely necessary in a patient with Parkinson's disease, Dolmatile 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 Dolmatile. 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 Dolmatile.

In patients requiring Dolmatile 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.

Dolmatile 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 dose should be reduced and titrated in small steps in cases of renal insufficiency.

Prolongation of the QT interval:

Dolmatile induces a prolongation of the QT interval. 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

Dolmatile 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.

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. Dolmatile should be used with caution in patients with stroke risk factors.

Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including Dolmatile. Unexplained infections or fever may be evidence of blood dyscrasia and requires immediate haematological investigation.

Dolmatile should be used with caution in hypertensive patients, especially in the elderly population, due to the risk of hypertensive crisis. Patients should be adequately monitored.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Even used as recommended, Dolmatile may cause sedation so that the ability to drive vehicles or operate machinery can be impaired.

The following 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 :

Uncommon: Leukopenia.

Not known: Neutropenia, agranulocytosis

Immune system disorders:

Not known: Anaphylactic reactions including urticaria, dyspnoea, hypotension and anaphylactic shock.

Endocrine disorders:

Common: Hyperprolactinaemia

Psychiatric disorders:

Common: Insomnia.

Not known: Confusion

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, and 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 three months. Antiparkinsonian medication is ineffective or may induce aggravation of the symptoms), convulsion.

Cardiac disorders:

Rare: Ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia.

Not known: electrocardiogram QT prolonged, cardiac arrest, torsade de pointes, sudden death.

Vascular disorders:

Uncommon: Orthostatic hypotension.

Not known: Venous embolism, pulmonary embolism, deep vein thrombosis.

Gastrointestinal disorders:

Uncommon: Salivary hypersecretion.

Hepatobiliary disorders:

Common: Hepatic enzyme increased

Skin and subcutaneous tissue disorders:

Common: Maculo-papular rash.

Musculoskeletal and connective tissue disorders:

Unknown: Torticollis, trismus.

Pregnancy, puerperium and perinatal conditions:

Not known: Extrapyramidal symptoms, drug withdrawal syndrome neonatal

Reproductive system and breast disorders:

Common: Breast pain, galactorrhoea.

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

Not known: Gynaecomastia.

General disorders and administration site conditions:

Common: Weight gain.

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.

Experience with Dolmatile 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.

Fatal outcomes have been reported mainly in combination with other psychotropic agents.

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.

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

Dolmatile is partly removed by haemodialysis.

There is no specific antidote to Dolmatile. 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, anti-parkinsonian drugs. Emetic drugs are unlikely to be effective. Coma needs appropriate nursing, and cardiac monitoring is recommended until the patient recovers. Emetic drugs are unlikely to be effective in Dolmatile overdosage.

Pharmacotherapeutic group: Psycholeptics; Benzamides,

ATC code: N05AL01

Dolmatile 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 Dolmatile hint at an important distinction between different types of dopamine receptors or receptor mechanisms in the brain.

Behaviourally and biochemically Dolmatile shares with 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 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 Dolmatile to striatal preparations in-vitro, compared to ³H-spiperone or ³H-haloperidol. These findings indicate a major differentiation between Dolmatile and classical neuroleptics, which lack such specificity.

One of the characteristics of Dolmatile 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 Dolmatile therapy.

Peak Dolmatile serum levels are reached 3 - 6 hours after an oral dose. The plasma half-life in man is approximately 8 hours. Approximately 40% Dolmatile is bound to plasma proteins. 95% of the compound is excreted in the urine and faeces as unchanged Dolmatile.

In long term animal studies with neuroleptic drugs including Dolmatile, 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.

None known

None