TRIFLUOPERAZINE 5 MG TABLETS - summary of medicine characteristics

Trifluoperazine 5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Trifluoperazine Hydrochloride 5.90 mg equivalent to Trifluoperazine 5 mg Also contains lactose, (95.10 mg per tablet), and sucrose, (80.10 mg per tablet), for full list of excipients, see 6.1.

3 PHARMACEUTICAL FORM

Sugar-coated tablet

Dark green sugar-coated tablet.

4.1 Therapeutic indications

Trifluoperazine is indicated in;

High Dosage:

The treatment of the symptoms of and for the prevention of relapse in schizophrenia and in other psychosis, especially paranoid psychosis, (but not depressive psychosis); mania and hypomania

As an adjunct in the short-term management of severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour

Low Dosage:

As an adjunct to the short-term management of anxiety states, depressive symptoms secondary to anxiety and agitation

Prophylaxis and treatment of nausea and vomiting associated with diffuse neoplastic disease, radiation sickness, and the emesis caused by drugs such as opioids, general anaesthetics, and cytotoxics

4.2 Posology and method of administration

ADULTS AND CHILDREN OVER 12 YEARS:

High Dosage:

In the treatment of the symptoms of schizophrenia, paranoid psychosis mania and hypomania, severe psychomotor agitation, excitement, violent or dangerously impulsive behaviour the recommended starting dose is 5 mg twice a day for physically fit adults. This dose may be increased after one week if necessary to 15 mg a day. Further increases may be made of 5 mg at 3-day intervals; this is the minimum time that should be allowed to elapse.

The dosage may be gradually reduced after satisfactory control has been achieved until an effective maintenance level is established.

When commencing treatment this should be undertaken under close supervision, and likewise, when it is necessary to increase dosage. Dosage requirement should always take into account the great variability of individual response.

After commencing treatment it may take several weeks for clinical improvement to become evident. There may be a delay before relapse after stopping treatment. It is essential that withdrawal from treatment should be gradual.

Low Dosage:

The recommended dosage when Trifluoperazine is used as an adjunct to the short-term management of anxiety is: 2–4 mg a day in divided doses. This dosage may be increased to a maximum of 6 mg per day in divided doses. Treatment should be commenced under close supervision as should any increase in dosage. Likewise the variability of individual response and dosage requirement must be borne in mind.

ELDERLY:

The starting dos e for the elderly or frail patients should be reduced by at least half

CHILDREN:

High Dosage:

For children aged less than 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

Low Dosage:

For children aged 6–12 years, up to a maximum of 4 mg a day given in divided doses

For children aged 3–5 years, up to a maximum of 1 mg daily given in divided doses

GENERAL:

Trifluoperazine should always be used for the minimum possible time at the minimal effective dosage level excepting where it is established that long-term administration for conditions such as schizophrenia is required.

Route of administration: Oral

4.3 Contraindications

Comatose states

CNS depression

Existing blood dyscrasias or bone marrow depression

Liver damage

Hypersensitivity to trifluoperazine, phenothiazines and/or to any of the other ingredients in the tablet

Phaeochromocytoma

4.4 Special warnings and precautions for use

Antipsychotic drugs should be used with caution in patients with cardiac arrhythmias; cardiovascular disease; renal impairment; epilepsy, conditions predisposing to epilepsy (e.g. alcohol withdrawal or brain damage); depression, Parkinson’s disease (may be exacerbated by antipsychotics); personal or family history of narrow angle glaucoma – hypothyroidism; myasthenia gravis; prostatic hypertrophy.

Caution is also required in severe respiratory disease and in patients with a history of jaundice.

As photosensitisation may occur with higher dosages, patients should avoid direct sunlight.

Trifluoperazine therapy should be discontinued as the first sign of clinical symptoms of tardive dyskinesia and Neuroleptic Malignant Syndrome, (see section 4.8).

Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.

Prescribing for the elderly

The balance of risks and benefit should be considered before prescribing antipsychotic drugs for elderly patients. In elderly patients with dementia, antipsychotic drugs are associated with a small increased risk of mortality and an increased risk of stroke or transient ischaemic attack. Furthermore, elderly patients are particularly susceptible to postural hypotension and to hyper- and hypothermia in hot or cold weather.

It is recommended that:

Antipsychotic drugs should not be used in elderly patients to treat mild to moderate psychotic symptoms.

Treatment should be reviewed regularly.

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.

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 factores for VTE should be identified before and during treatment with trifluoperazine and preventative measures undertaken.

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

4.5 Interaction with other medicinal products and other forms of interaction Trifluoperazine can increase the central nervous system depression produced by other CNS depressant drugs including alcohol, hypnotics, sedatives, or strong analgesics.

There is an increased risk of ventricular arrhythmias when trifluoperazine is given with other drugs that prolong the QT interval. It is recommended that concomitant use with antiarrhythmics (amiodarone, disopyramide), tricyclic antidepressants, antibacterials (erythromycin, sparfloxacin, clarithromycin, moxifloxacin), antipsychotics (pimozide, halofantrine, sertindole, thioridazine), some antihistamines (astemizole, terfenadine), some antimalerials and other agents that are known prolong the QT interval (pentamidine isetionate, sotalol, droperidol, atomoxetine, methodone, quinidine) should be avoided.

Interactions between antipsychotics and tricyclic antidepressants may take the form of additive antimuscarinic effects as well. There is also an increased risk of this effect when phenothiazines are given with antimuscarinic agents. Additive antimuscarinic activity may be a significant risk especially in the elderly.

Enhanced hypotensive effects have been observed when trifluoperazine is given with antihypertensives (e.g. ACE inhibitors, minoxidil), calciumchannel blockers, diuretics, general anaesthetics or opioid analgesics, and dosage adjustments may be necessary.

There is an increased risk of convulsions when antipsychotics given with tramadol.

There is an increased risk of extra-pyramidal side effects when phenothiazines are given with lithium, metoclopramide, methyldopa, amantadine or tetrabenazine.

The plasma concentrations of antipsychotics are possibly increased by ritonavir. It is recommended that drug concentrations and/or adverse effects are monitored is required when trifluoperazine is used with ritonavir.

The effects of antipsychotics are possibly enhanced by cimetidine, and reduced by memantine.

Trifluoperazine may antagonise the action of adrenaline and-other sympathomimetic agents and reverses the blood-pressure-lowering effects of adrenergic-blocking agents such as guanethidine and clonidine.

Trifluoperazine may impair the metabolism of tricyclic antidepressants, the anti-Parkinson effects of levodopa, bromocriptine, cabergoline, pergolide and apomorphine, and the anticonvulsant effects of anticonvulsants, antiepileptics (carbamazepine, ethosuximide, oxcarbazepine, phenytoin, primidone and valproate), and barbiturates.

Trifluoperazine may also possibly affect the ability of sulphonylureas to control diabetes, and possibly enhance the effects of sodium oxybate.

The absorption of phenothiazines is reduced by antacids and possibly by kaolin.

Undesirable anticholinergic effects can be enhanced by anti-Parkinson (e.g. benzhexol) or other anticholinergic drugs (e.g. orphenedrine, benztropine).

There is an increased risk of CNS toxicity when antipsychotics are given with Sibutramine. The possiblily increased risk of neurotoxicity with lithium should also be borne in mind.

Desferrioxamine should not be used in combination with trifluoperazine. Avoidance of trifluoperazine is also advised for patients receiving artemether, pramipexole, ropinirole, rotigotine, due to antagonism of their effect.

4.6 Fertility, Pregnancy and lactation

Pregnancy:

Trifluoperazine should be avoided in pregnancy, unless thought to be essential by health professionals.

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.

Lactation:

Trifluoperazine has been shown to pass into the milk of lactating dogs. Animal studies also indicate possible adverse effects of these drugs on the developing nervous system therefore it is advisable to either avoid unless absolutely necessary, or to discontinue breast-feeding during treatment.

4.7 Effects on ability to drive and use machines

Patients should be warned of the risks of sedation and advised not to drive or operate machinery during treatment, until their susceptibility is known.

It is advisable to warn that the effects of alcohol are enhanced.

4.8 Undesirable effects

Blood and the lymphatic system disorders:

Blood dyscrasias, (agranulocytosis has been reported very rarely, most commonly in the first three months of treatment, but occasionally later. Blood counts should be performed if the patient develops signs of a persistent infection. Transient leucopenia can also occur.)

Pancytopenia; thrombocytopenia

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

Immune system disorders:

Hypersensitivity reactions include urticaria, exfoliative dermatitis, erythema multiforme and contact sensitivity. A syndrome resembling systemic lupus erythematosus has been reported. Jaundice has occurred, (also see Hepatobiliary disorders below), and probably has an immunological origin.

Endocrine disorders:

Hyperprolacti­naemia, which may cause effects such as menstrual disturbances (oligo- or amenorrhoea), galactorrhoea, and gynaecomastia

Impaired sexual function, including impotence, ejaculation problems and priapism; weight gain

Metabolism and nutrition:

Anorexia; raised serum cholesterol; rarely hyperglycaemia

Psychiatric disorders:

Apathy; agitation; excitement; insomnia; confusion

Trifluoperazine, even in low dosage in susceptible (especially non-psychotic) individuals, may cause unpleasant subjective feelings of being mentally dulled or slowed down

Nervous system disorders:

Extrapyramidal symptoms are the most troublesome. They occur most frequently, especially at doses exceeding 6 mg daily, but sometimes at low dosages. They are easy to recognise but cannot be predicted accurately because they depend on the dose, the type of drug, and on individual susceptibility.

Extrapyramidal symptoms consist of:

parkinsonian symptoms (including tremor), which may occur more commonly in adults or the elderly and may appear gradually;

Anti-Parkinson agents should not be prescribed routinely, because of the possible risks of aggravating anticholinergic side effects of Trifluoperazine, of precipitating toxic-confusional states or of impairing its therapeutic efficacy. They should only be given as required.

Parkinsonian symptoms remit if the drug is withdrawn and may be suppressed by the administration of antimuscarinic drugs. However, routine administration of such drugs is not justified because not all patients are affected and because they may unmask or worsen tardive dyskinesia.

dystonia (abnormal face and body movements, oculogyric crises have also been reported) and dyskinesia, which occur more commonly in children or young adults and appear early in treatment, after only a few doses;

akathisia (restlessness), which characteristically occurs after large initial doses and may resemble an exacerbation of the condition being treated;

tardive dyskinesia (it is characterised by rhythmic, involuntary movements of tongue, face, and jaw, e.g. abnormal writhing movements or protrusions of the tongue with lip-smacking, puckering and chewing movements and facial grimaces), which usually develops on long-term therapy or with high dosage, but it may develop on short-term treatment with low doses-shortlived tardive dyskinesia may occur after withdrawal of the drug.

Choreoathetoid movements of the extremities or repetitive movements of the neck or trunk may accompany the orofacial dyskinesia or can occur alone. Tardive dyskinesia is of particular concern because it may be irreversible on withdrawing therapy and treatment is usually ineffective. However, some manufacturers suggest that drug withdrawal at the earliest signs of tardive dyskinesia (fine vermicular movements of the tongue) may halt its full development. Tardive dyskinesia occurs fairly frequently, especially in the elderly, and treatment must be carefully and regularly reviewed.

Neuroleptic malignant syndrome (hyperthermia, fluctuating level of consciousness, muscle rigidity, and autonomic dysfunction with pallor, tachycardia, labile blood pressure, sweating, and urinary incontinence) is a rare but potentially fatal side-effect of some drugs. Discontinuation of the antipsychotic is essential because there is no proven effective treatment, but symptomatic treatment including cooling, bromocriptine, and dantrolene have been used. The syndrome, which usually lasts for 5–7 days after drug discontinuation, may be unduly prolonged if depot preparations have been used.

Drowsiness; sedation, (especially in the elderly); anti-muscarinic symptoms, (such as dry mouth, constipation, difficulty with micturition, and blurred vision), particularly with high dosage and at the start of treatment

Impaired alertness, (especially at the start of treatment), this effect may be potentiated by alcohol

Convulsions; dizziness; headache; epileptic fits

Eye disorders:

Permanent deposits, leading to impairment of vision, may develop in the lens. Epithelial keratophathy has been reported

Corneal and lens opacities; purplish pigmentation of the cornea, conjunctiva, and retina

Very rarely, precipitation of angle-closure glaucoma

Cardiovascular disorders:

The effects of phenothiazines on the heart are dose-related.

Cardiovascular symptoms (such as hypotension, tachycardia, and arrhythmias); ECG changes (prolongation of the QT interval and T-wave changes have been reported commonly in patients treated with moderate to high dosage; they are reversible on reducing the dose. In a very small number of cases, they have been reported to precede serious arrhythmias, including ventricular tachycardia and fibrillation, which have also occurred after overdosage, cases of sudden death have also occurred).

Postural hypotension is a dose-related side-effect and is liable to cause dangerous falls in the elderly, particularly after intramuscular injections

Respiratory, thoracic and mediastinal disorders:

Nasal congestion

Gastrointestinal disorders:

Gastro-intestinal disturbances; nausea

Hepato-biliary disorders:

Very rarely, obstructive jaundice associated with stasis in biliary canaliculi; Transient abnormalities of liver function tests may occur in the absence of jaundice

Skin and subcutaneous tissue disorders:

Photosensitisation rarely, causes increased susceptibility to sunburn and patients should be warned to avoid excessive exposure, contact sensitisation and rashes, increased melanin pigmentation of the skin, which eventually may develop into a purplish pigmentation of the skin

Pregnancy, puerperium and perinatal conditions:

Drug withdrawal syndrome neonatal (see 4.6), frequency: not known.

General disorders and administrative site disorders:

Oedema, which may be prevented by reduction in dosage; hyperpyrexia

Interference with temperature regulation is a dose-related side-effect and is liable to cause hypothermia or hyperthermia in the elderly. Hypothyroid patients may be particularly susceptible to hypothermia. The hazard of hyperthermia may be increased by especially hot or humid weather or by drugs, such as anti-Parkinson agents, which impair sweating.

In schizophrenia, the response to antipsychotic drug treatment may be delayed. If drugs are withdrawn, recurrence of symptoms may not become apparent for several weeks or months.

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

Gradual withdrawal is advisable.

4.9 Overdose

Phenothiazines cause less depression of consciousness and respiration than other sedatives. Hypotension, hypothermia, sinus tachycardia, and arrhythmias may complicate poisoning. Dystonic reactions can occur with therapeutic doses, and convulsions may occur in severe cases.

There is no specific antidote. After an overdose, patients should be managed with intensive symptomatic and supportive therapy. Activated charcoal should be given by mouth if a substantial amount of the phenothiazine has been taken within 1 hour of presentation, provided that the airway can be protected, emptying the stomach by gastric lavage has sometimes been recommended. Dialysis is of little or no value in poisoning by phenothiazines.

Acute hypotension should be countered by raising the patient’s legs, or in severe cases by intravascular volume expansion. An inotrope such as dopamine may be considered in refractory cases. If a vasoconstrictor is considered necessary in the management of phenothiazine-induced hypotension the use of adrenaline or other sympathomimetics with high beta-adrenergic agonist properties should be avoided since the alpha-blocking effects of phenothiazines may impair the usual alpha-mediated vasoconstriction of these drugs, resulting in unopposed beta-adrenergic stimulation and increased hypotension.

The symptomatic treatment of central nervous depression should be instituted including the administration of antibiotics to prevent bronchopneumonia. Extrapyramidal symptoms may be treated with anticholinergic antiParkinsonian drugs. Dystonic reactions are rapidly abolished by injection of drugs such as procyclidine or diazepam.

Arrhythmias may respond to correction of hypoxia, acidosis, and other biochemical abnormalities, but specialist advice should be sought if arrhythmias result from a prolonged QT interval; the use of some anti-arrhythmic drugs can worsen such arrhythmias.

It is advisable to institute cardiac monitoring because of the likelihood of the occurrence of cardiac arrhythmias particularly when body temperature falls below 30°C. A special watch should also be kept for the development of bladder and intestinal distension.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Trifluoperazine is a piperazine phenothiazine antipsychotic (ATC Code: N05A B06). It has 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.

5.2 Pharmacokinetic properties

Trifluoperazine is readily absorbed from the gastrointestinal tract and is subject to first-pass metabolism in the gut wall. It is also excessively metabolised in the liver and excreted in the urine and faeces in the form of active and inactive metabolites.

Plasma half-life is only about 2 hours but the terminal elimination phase can be up to 3 weeks.

Trifluoperazine is extensively bound to plasma protein. The drug crosses the blood/brain barriers and its metabolites also cross the placental barriers and are excreted in milk.

5.3 Preclinical safety data

No relevant information additional to that contained elsewhere in the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipientsTablet Core

Lactose

Maize Starch

Pregelatinised Maize Starch

Magnesium Stearate

Shellac

Talc

Titanium Dioxide

Sucrose

Povidone

Opalux AS-F-5922 Green

– Sucrose

– FD&C Blue #2 / Indigo Carmine Lake

– Quinoline Yellow Lake

– Titanium Dioxide

– Sodium Benzoate

Beeswax

Carnauba Wax

6.2 Incompatibilities

Not applicable

6.3 Shelf life

36 months

6.4 Special precautions for storage

Do not store above 25°C. Keep the container tightly closed.

6.5 Nature and contents of container

High density polyethylene/po­lypropylene containers with polythene/poly­propylene lids and polyurethane/po­lythene inserts

Pack sizes: 28, 30, 50, 56, 60, 84, 100, 112, 250, 500 and 1000.

6.6 Special precautions for disposal

Not applicable

7 MARKETING AUTHORISATION HOLDER

Genethics Europe Limited

41–43 Klimentos,

Klimentos Tower,

Nicosia 1061,

Cyprus

8 MARKETING AUTHORISATION NUMBER(S)

PL 42976/0011

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

12/06/2009