SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Trifluoperazine 5mg/5ml Oral Solution

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Trifluoperazine Hydrochloride BP equivalent to trifluoperazine 5mg/5ml

Excipient(s) with known effect:

Methyl hydroxybenzoate (E218) 6mg/5ml Propyl hydroxybenzoate (E216) 1.5mg/5ml Sorbitol Solution (E420) 0.5ml/5ml Liquid Maltitol (E965) 1.25ml/5ml

For the full list of excipients, see section 6.1

3.    Pharmaceutical Form Oral solution.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Trifluoperazine is a piperazine phenothiazine tranquilliser with potent antipsychotic, anxiolytic and anti-emetic activity, and a pharmacological profile of moderate sedative and hypotensive properties, and fairly pronounced tendency to cause extrapyramidal reactions.

Low Dosage

Trifluoperazine is indicated as an adjunct in the short term management of anxiety states, depressive symptoms secondary to anxiety, and agitation. It is also indicated in the symptomatic treatment of nausea and vomiting.

High Dosage

Trifluoperazine is indicated for the treatment of symptoms and prevention of relapse in schizophrenia and in other psychoses, especially of the paranoid type, but not in depressive psychoses. It may also be used as an adjunct in the short term management of severe psychomotor agitation and of dangerously impulsive behaviour, for example, mental subnormality.

4.2. Posology and method of administration

Posology

Adults

Low Dosage: 2- 4 mg a day given in divided doses, according to the severity of the patient’s condition. If necessary, dosage may be increased to 6mg a day but above this level, extrapyramidal symptoms are more likely to occur in some patients.

High dosage: The recommended starting dose for physically fit adults is 5mg twice a day; after a week this may be increased to 15mg a day. If necessary, further increases of 5mg may be made at three day intervals, but not more often. When satisfactory control has been achieved, dosage should be reduced gradually until an effective maintenance level has been established. As with all major tranquillisers, clinical improvement may not be evident for several weeks after starting treatment, and there may also be delay before recurrence of symptoms after stopping treatment. Gradual withdrawal from high dosage treatment is advisable.

Elderly

Reduce starting dose in elderly and frail patients by at least half.

Paediatric Population

Low Dosage: For children aged 3 - 5 years - up to 1mg a day given in divided doses.

For children aged 6 - 12 years - the dosage may be increased to a maximum of 4mg a day.

High Dosage: For children aged under 12 years - the initial oral dosage should not exceed 5mg a day, given in divided doses. Any subsequent increase should be made with caution, at intervals of not less than three days and taking into account age, body weight and severity of symptoms.

Method of administration

For oral administration only.

4.3.    Contraindications

Do not use Trifluoperazine in comatose patients, particularly if associated with other central nervous system depressants, or in those with existing blood dyscrasias or known liver damage, or in those hypersensitive to the active substance or to any of the excipients listed in section 6.1. Patients with uncontrolled cardiac decompensation should not be given trifluoperazine.

4.4.    Special warnings and precautions for use

Trifluoperazine should be discontinued at the first sign of clinical symptoms of tardive dyskinesia and Neuroleptic Malignant Syndrome.

Patients on long term phenothiazine therapy require regular and careful surveillance with particular attention to tardive dyskinesia and possible eye changes, blood dyscrasias, liver dysfunction and myocardial conduction defects, particularly if other concurrently administered drugs have potential effects in these systems.

Care should be taken when treating elderly patients, and initial dosage should be reduced. Such patients can be especially sensitive, particularly to extrapyramidal and hypotensive effects. Patients with cardiovascular disease including arrhythmias should also be treated with caution. Because Trifluoperazine may increase activity, care should be taken in patients with angina pectoris. If an increase in pain is noted, the drug should be discontinued. Patients who have demonstrated bone marrow suppression or jaundice with a phenothiazine should not be re-exposed to trifluoperazine unless in the judgement of the physician the potential benefits of the treatment outweigh the possible hazards.

In patients with Parkinson’s disease, symptoms may be worsened, and the effects of levodopa reversed. Since phenothiazines lower the convulsive threshold, patients with epilepsy should be treated with caution, and metrizamide avoided. Although Trifluoperazine has minimal anticholinergic activity, this should be borne in mind when treating patients with narrow angle glaucoma, myasthenia gravis or prostatic hypertrophy. Nausea and vomiting as a sign of organic disease may be masked by the anti-emetic action of Trifluoperazine.

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 is not known. Trifluoperazine should be used with caution in patients with risk factors for stroke.

Caution should be used in patients with cardiovascular disease or family history of QT prolongation. Concomitant use of neuroleptics should be avoided.

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 Trifluoperazine and preventive measures undertaken.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of high doses 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.

Phenothiazines should be used with care in extremes of temperature since they may affect body temperature control.

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.

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

Ingredients in the formulation The medicine contains:

■    sorbitol and maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

■    Methyl and propyl hydroxybenzoate. These may cause allergic reactions (possibly delayed).

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

Potentiation may occur if antipsychotic drugs are combined with CNS depressants such as alcohol, hypnotics, anaesthetics and strong analgesics, or with antihypertensives or other drugs with hypotensive activity, anticholinergics or antidepressants. Phenothiazines may antagonise the action of Guanethidine and Levodopa. Trifluoperazine may aggravate Parkinsonism and antagonise the action of levodopa. They may lower the convulsive threshold. Hence patients with epilepsy should be treated with caution.

Serum levels of phenothiazine can be reduced to non-therapeutic concentrations by concurrent administration of lithium. Dosage increases may be needed. Desferrioxamine should not be used in combination with Trifluoperazine, since prolonged unconsciousness has occurred after combination with the related prochlorperazine.

Trifluoperazine may diminish the effect of oral anticoagulants.

Severe extrapyramidal side-effects or neurotoxicity have been observed in patients concurrently treated with lithium and trifluoperazine. Sleep walking has been described in some patients taking phenothiazines and lithium.

Antacids can reduce the absorption of phenothiazines.

Phenothiazines increase the risk of ventricular arrhythmias when given with drugs which prolong the Q-T interval, drugs causing electrolyte imbalances.

4.6.    Fertility, pregnancy and lactation

Trifluoperazine has been available since 1958. There are some animal studies that indicate a teratogenic effect, but results are conflicting. There is no clinical evidence (including follow-up surveys in over 800 women who had taken low-dosage Trifluoperazine during pregnancy) to indicate that trifluoperazine has a teratogenic effect in man. Nevertheless, drug treatment should be avoided in pregnancy unless essential, especially during the first trimester. Trifluoperazine crosses the placenta and passes into the milk of lactating dogs. Breast feeding should only be allowed at the discretion of the physician

Neonates exposed to antipsychotics (including Trifluoperazine) 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.

4.7.    Effects on ability to drive and use machines

Trifluoperazine may cause side effects including drowsiness, dizziness and visual disturbances which interfere with the ability to drive and operate machinery. Do not drive or use machines when you first start to take this medicine until you are certain that you are not getting these side effects.

4.8.    Undesirable effects

Lassitude, drowsiness, dizziness, transient restlessness, insomnia, dry mouth, blurred vision, muscular weakness, anorexia, mild postural hypotension, skin reactions including photosensitivity reactions, weight gain, oedema and confusion may occasionally occur. Tachycardia, constipation, urinary hesitancy and retention and hyperpyrexia have been reported very rarely. Adverse reactions tend to be dose related and to disappear.

Hyperprolactinaemia may occur at higher dosages with associated effects such as galactorrhoea, amenorrhoea or gynaecomastia; certain hormone dependant breast neoplasms may be affected.

Phenothiazines can produce ECG changes with prolongation of the QT interval and T-wave changes; ventricular arrhythmias (VF, VT (rare)), sudden unexplained deaths; cardiac arrest and Torsades de pointes have been reported. Such effects are rare with Trifluoperazine.

Serious arrhythmias have been reported.

In some patients, especially non-psychotic patients, Trifluoperazine even at a low dosage may cause unpleasant symptoms of being dulled or, paradoxically, of being agitated. Extrapyramidal symptoms are rare at oral daily dosages of 6mg or less; they are considerably more common at higher dosage levels. These symptoms include Parkinsonism, akathisia with motor restlessness and difficulty in sitting still and acute dystonia or dyskinesia, which may occur early in treatment and may present with torticollis facial grimacing, trismus, tongue protrusion and abnormal eye movements including oculogyric crises. These effects are likely to be particularly severe in children. Such reactions may often be controlled by reducing the dosage or by stopping medication. In more severe dystonic reactions, an anticholinergic antiparkinsonism drug should be given.

Tardive dyskinesia of the facial muscles, sometimes with involuntary movements of the extremities, has occurred in some patients on long term, high dosage and, more rarely, low dosage phenothiazine therapy, including Trifluoperazine. Symptoms may appear for the first time either during or after a course of treatment; they may become worse when treatment is stopped. The symptoms may persist for many months or even years, and while they gradually disappear in some patients, they appear to be permanent in others. Patients have most commonly been elderly, female or with organic brain damage. Particular caution should be observed in treating such patients. Periodic gradual reduction of dosage to reveal persisting dyskinesia has been suggested, so that treatment may be stopped if necessary. If tardive dyskinesia occurs, trifluoperazine should be discontinued.

Anticholinergic antiparkinsonism agents may aggravate the condition. Since the occurrence of tardive dyskinesia may be related to length of treatment and dosage, Trifluoperazine should be given for as short a time and at as low a dosage as possible. The neuroleptic malignant syndrome is a rare but occasionally fatal complication of treatment with various neuroleptic drugs, and is characterised by hyperpyrexia, muscle rigidity, altered consciousness and autonomic instability. Intensive symptomatic treatment, following discontinuation of Trifluoperazine, should include cooling. Intravenous dantrolene has been suggested for muscle rigidity.

Mild cholestatic jaundice and blood dyscrasias such as agranulocytosis, pancytopenia, leucopenia and thrombocytopenia have been reported very rarely.

Signs of persistent infection should be investigated.

Very rare cases of skin pigmentation and lenticular opacities have been reported with Trifluoperazine.

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

Withdrawal reactions have been reported in association with antipsychotic drugs (see 4.4)

Pregnancy, puerperium and perinatal conditions:

Not known: Drug withdrawal syndrome neonatal (see 4.6).

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; website www.mhra.gov.uk/yellowcard

4.9 Overdose

Signs and symptoms will be predominantly extrapyramidal; hypotension may occur. Treatment consists of gastric lavage together with supportive and symptomatic measures. Do not induce vomiting. Extrapyramidal symptoms may be treated with an anticholinergic antiparkinsonism drug. Treat hypotension with fluid replacement; if severe or persistent, noradrenaline may be considered. Adrenaline is contra-indicated.

5.1. Pharmacodynamic properties ATC code: N05AB06

Trifluoperazine is one of the phenothiazine class of compounds and as such has many pharmacodynamic effects which relate to its therapeutic actions and side effects. The most notable action of phenothiazines is antagonism at dopamine receptors in the CNS. It is hypothesised that this action in the limbic system and associated areas of cerebral cortex is the basis of the antipsychotic action of phenothiazines, whilst in the medullary chemoreceptor trigger zone it appears to be responsible for the antiemetic effect of these agents. In addition, dopamine antagonism in the basal ganglia appears to be involved in some of the extrapyramidal side-effects of phenothiazines, whilst blockage of the dopaminergic inhibition of prolactin release from the anterior pituitary gland is thought to lead to hyperprolactinaemia.

Other central actions of phenothiazines include sedation and inhibition of the function of the hypothalmic heat regulatory centre. Phenothiazines also lower the seizure threshold. Central actions of phenothiazines also affect the cardiovascular system, as does their antagonism of peripheral a - adrenergic receptors, which can cause hypotension.

Phenothiazines also have anti - muscarinic activity which causes certain side effects.

Trifluoperazine is one of the piperazine sub-class of phenothiazine drugs whose members have fewer sedative, antimuscarinic and hypotensive side - effects but more extrapyramidal side effects than other types of phenothiazines.

5.2 Pharmacokinetic properties

The pharmacokinetics for trifluoperazine are typical of phenothiazines such as chlorpromazine.

Absorption: It is readily absorbed from the gastrointestinal tract with peak plasma levels being reached from 1.5 to 6.0 hours after ingestion. A high interindividual variation in bioavailability has been consistently reported.

Distribution: In the blood, trifluoperazine is highly bound to plasma proteins. It probably penetrates the placental barrier and enters breast milk like chlorpromazine.

Biotransformation: Several metabolites of trifluoperazine have been identified, including an N-oxide, a sulphoxide and a 7-hydroxy derivative. The N-oxide is thought to be the main metabolite and possibly active. This and the sulphoxide metabolite are thought to be extensively metabolised pre-systemically (i.e. in the gut and/or liver), whilst the 7-hydroxy derivative appears to undergo no such metabolism.

Elimination: The elimination of trifluoperazine from the blood is multiphasic with an alpha phase elimination half-life of about 3.6 hours and a terminal elimination half-life of about 22 hours. Elimination occurs via bile and urine.

5.3 Preclinical Safety Data

None Stated.

6.    PHARMACEUTICAL PARTICULARS

6.1.    List of Excipients

Propylhydroxybenzoate, methylhydroxybenzoate, propylene glycol, sorbitol solution 70%, Liquid Maltitol, ascorbic acid, lime and aniseed flavour, caramel E150 and purified water.

6.2.    Incompatibilities

None.

6.3.    Shelf life

6 months unopened 1 month after opening

6.4.    Special Precautions for Storage

Store below 25 °C, protected from light.

6.5.    Nature and contents of container

Bottles:    Amber (Type III) glass

Closure:    HDPE EPE wadded, tamper evident, child resistant.

Capacity:    150ml

6.6.    Instructions for Use, Handling and Disposal

Keep out of the reach of children.

7.    MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Limited

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8.    MARKETING AUTHORISATION NUMBER(S)

PL 00427/0118

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/07/2008

10    DATE OF REVISION OF THE TEXT

17/08/2016