Trifluoperazine Tablets Bp 1mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Trifluoperazine Tablets BP 1mg.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains trifluoperazine hydrochloride BP 1.2mg equivalent to trifluoperazine 1mg.
3 PHARMACEUTICAL FORM
Coated tablets for oral administration.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
In 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.
In high dosage, trifluoperazine is indicated for the treatment 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 shortterm management of severe psychomotor agitation and of dangerous impulsive behaviour in, for example, mental subnormality.
4.2 Posology and method of administration
Adults:
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Low dosage: |
2mg to 4mg daily in divided doses according to the severity of the patient’s condition. If necessary, dosage may be increased to 6mg daily, but above this level extrapyramidal symptoms are more likely to occur in some patients. |
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High dosage: |
The recommended starting dose for physically fit adults is 5mg twice daily; after a week this may be increased to 15mg daily. If necessary, further increases of 5mg may be made at 3-day |
intervals, but not more often. When satisfactory control has been achieved, dosage may be reduced gradually until an effective maintenance level has been established.
Elderly:
Reduce the starting dose in elderly or frail patients by at least half.
Children:
The tablet presentation is unsuitable for children under 12 years, for whom a liquid presentation should be used.
4.3 Contraindications
The use of trifluoperazine is contraindicated in the following instances;
• in comatose patients
• in patients with existing blood dyscrasias or known liver damage
• in those hypersensitive to the active ingredient, other excipients in the product or related compounds.
Patients with uncontrolled cardiac decompensation should not be given Trifluoperazine.
4.4 Special warnings and precautions for use
Trifluoperazine should be discontinued as 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) or family history of QT prolongation should be treated with caution.
The use of concomitant neuroleptics should be avoided.
Because trifluoperazine may increase activity, care should be taken with patients with angina.
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 treatment outweigh the possible hazard.
In patients with Parkinson’s disease, symptoms may be worsened, and the effect of levodopa reversed.
Since phenothiazines may 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 and prostatic hypertrophy.
Nausea and vomiting as a sign of organic disease may be masked by the antiemetic action of trifluoperazine.
Acute withdrawal symptoms including nausea, vomiting 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, a gradual withdrawal is advisable.
Phenothiazines should be used with care in extremes of temperature since they may affect body temperature control.
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
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.
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. An increased risk cannot be excluded for other antipsychotics or other patient populations. Trifluoperazine should be used with caution in patients with risk factors for stroke.
4.5 Interaction with other medicinal products and other forms of interaction
Potentiation may occur with CNS depressants such as alcohol, hypnotics and strong analgesics or with antihypertensives or other drugs with hypotensive activity, anticholinergics or antidepressants.
The threshold of anticonvulsants such as Oxcarbazepine, Carbamazepine, Ethosuximide, Phenytoin, Valproate and Barbiturates maybe lowered if coadministered with Trifluoperazine.
There is an increase risk of arrhythmias if Trifluoperazine is co-administered with Terfenadine, tricyclic antidepressants and anti-arrhythmics.
Trifluoperazine has an enhanced hypotensive effect with general anaesthetics.
Trifluoperazine may reverse the effect of levodopa.
Trifluoperazine may antagonise the action of guanethidine
Antacids will reduce absorption.
Ritonavir may increase the plasma concentration of Trifluoperazine.
Metrizamide should be avoided.
Increased toxicity of myelosuppressive / cytotoxic drugs, there maybe more of a risk of agranulocytosis.
The concomitant use of QT prolonging drugs should be avoided.
The use of drugs that can cause an electrolyte imbalance and metabolic inhibitors (CYP...) where known should be used with caution.
Avoid drugs that depress leucopoiesis.
Serum levels of phenothiazine can be reduced to non-therapeutic concentrations by concurrent administration of lithium. Desferrioxamine should not be used in combination with trifluoperazine, since prolonged unconsciousness has occurred after combination with the related prochiorperazine.
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.
4.6 Fertility, Pregnancy and lactation
There is no evidence to show any hazard to the foetus associated with trifluoperazine. Nevertheless, drug treatment should be avoided in pregnancy, unless essential.
Trifluoperazine passes into the milk of lactating dogs, so breast-feeding should only be undertaken with care.
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 drowsiness. Patients should be advised not to drive or operate machinery during treatment until their individual susceptibility is known.
4.8 Undesirable effects
General side effects include lassitude, drowsiness, apathy, dizziness, transient restlessness (akathisia), insomnia, gastrointestinal disturbances, confusion, muscular weakness, anorexia, convulsions, mild postural hypotension, skin reactions including photosensitivity reactions, hyperpyrexia and oedema.
There are also antimuscarinic symptoms (such as dry mouth, constipation, urinary hesitation and retention and blurred vision), adverse reactions tend to be dose related and to disappear.
Cardiovascular side effects include tachycardia and in addition Phenothiazines can produce ECG changes with prolongation of the QT interval and T-wave changes; serious arrhythmias, cardiac arrest and Torsades de pointes have been reported rarely.
Rare cases of sudden and unexplained death have been reported.
Endocrine related side effects include, weight gain and also hyperprolactinaemia may occur at higher dosages with associated effects such as galactorrhoea, or amenorrhoea or gynaecomastia; certain hormone-dependent breast neoplasms may be affected.
Blood dyscrasias such as agranulocytosis, pancytopenia, leucopenia and thrombocytopenia have been reported rarely.
Trifluoperazine even at low dosage may cause unpleasant symptoms of being lacklustre or paradoxically of being agitated.
Extrapyramidal symptoms are rare at daily dosages of 6mg or less; they are considerably more common at higher 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 (which in some cases maybe irreversible), sometimes with involuntary movements of the extremities and parkinsonian symptoms (including tremours), has occurred in some patients.
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.
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 total cumulative dosage, ''trifluoperazine'' should be given for as short a time and at as low a dosage as possible.
Signs of persistent infection should be investigated.
Skin reactions including photosensitivity reactions, oedema and mild cholestatic jaundice may occasionally occur.
Very rare cases of skin pigmentation and lenticular opacities have been reported with trifluoperazine.
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 should include cooling. Intravenous dantrolene has been suggested for muscle rigidity.
Cholestatic jaundice, and blood dyscrasias such as agranulocytosis, pancytopenia, leucopenia and thrombocytopenia have been reported very rarely. Signs of persistent infection should be investigated.
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 antipyschotic drugs (see 4.4).
These adverse effects are class effects of neuroleptics.
System Organ Class: Pregnancy, puerperium and perinatal conditions. Adverse Drug Reaction / Frequency: Drug withdrawal syndrome neonatal (see
4.6) / not known.
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
4.9 Overdose
Signs and symptoms will be predominately 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 anticholmergic anti-Parkinsonism drug. Treat hypotension with fluid replacement; if severe or persistent noradrenaline may be considered. Adrenaline is contraindicated, and dobutamine should be considered.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
A piperazine phenothiazine tranquilliser with potent antipsychotic, anxiolytic and anti-emetic properties, and fairly pronounced tendency to cause extrapyramidal reactions.
5.2 Pharmacokinetic properties
Trifluoperazine is readily absorbed from the gastrointestinal tract, but is subject to considerable first-pass metabolism in the gut wall. It is also extensively metabolised m the liver and is excreted in the urine and faeces in the form of numerous active and inactive metabolites; there is evidence of enterohepatic recycling. Owing to the first-pass effect, plasma concentrations following oral administration are much lower than those following intramuscular injection. Moreover, there is very wide intersubject variation in plasma concentration. Paths of metabolism include hydroxylation and conjugation with glucuronic acid, N-oxidation, oxidation of a sulphur atom, and dealkylation. It is extensively bound to plasma proteins. It is widely distributed in the body and crosses the blood-brain barrier to achieve higher concentrations in the brain than in the plasma. Together with its metabolites it also crosses the placental barrier and is excreted in the milk.
5.3 Preclinical safety data
No additional data provided. The pre-clinical safety of trifluoperazine is already well documented.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Cor starch, lactose, polyvinylpyrrolidone, magnesium stearate, talc, Opaseal* (containing industrial methylated spirit, polyvivinyl acetate phthalate, purified water and stearic acid), sucrose, titanium dioxide and Opalux Blue* (containing sucrose, purified water, titanium dioxide, indigo carmine aluminium lake - E132, polyvinylpyrrolidone and sodium benzoate - E211
6.2 Incompatibilities
None known.
6.3 Shelf life
36 months.
6.4 Special precautions for storage
Store in a cool dry place. Protect from light.
6.5 Nature and contents of container
Securitainers or opaque screw-cap plastic containers or poly-bag lined lever lid tins. Pack sizes - 50, 100, 112, 250, 500 and 1,000.
6.6 Special precautions for disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Ennogen Pharma Limited
Unit G4 Riverside Industrial Estate
Riverside Way
Dartford
Kent
DA1 5BS
8 MARKETING AUTHORISATION NUMBER(S)
PL 40147/0078
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20/01/1993 / 12/01/2007
10 DATE OF REVISION OF THE TEXT
15/07/2015