Fluanxol Tablets 0.5 mg

Fluanxol Tablets 1 mg

0.5 mg tablets (containing 0.584 mg flupentixol dihydrochloride equivalent to0.5 mg flupentixol base).

1 mg tablets (containing 1.168 mg flupentixol dihydrochloride equivalent to1 mg flupentixol base).

Round, biconvex, ochre-yellow, sugar-coated tablets.

Symptomatic treatment of depression (with or without anxiety).

Route of administration: Oral.

Adults

The standard initial dosage is 1 mg as a single morning dose. After one week the dose may be increased to 2 mg if there is inadequate clinical response. Daily dosage of more than 2 mg should be in divided doses up to a maximum of 3 mg daily.

Elderly

Elderly patients should receive half the recommended dosages. The standard initial dosage is 0.5 mg as a single morning dose. After one week, if response is inadequate, dosage may be increased to 1 mg once a day.

Caution should be exercised in further increasing the dosage but occasional patients may require up to a maximum of 1.5 mg a day which should be given in divided doses.

Children

Not recommended for children.

Reduced renal function

Flupentixol has not been studied in renal impairment. Increased cerebral sensitivity to antipsychotics has been noted in severe renal impairment (see section 4.4).

Reduced hepatic function

Flupentixol has not been studied in hepatic impairment. It is extensively metabolised by the liver and particular caution should be used in this situation and serum level monitoring is advised (see section 4.4).

Patients often respond within 2-3 days. If no effect has been observed within one week at maximum dosage the drug should be withdrawn.

Hypersensitivity to the active substance or to any of the excipients (see section 6.1). Severe depression requiring ECT or hospitalisation, states of excitement or overactivity, including mania.

Circulatory collapse, depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates), coma.

Not recommended for excitable or agitated patients.

Caution should be exercised in patients having: liver disease; cardiac disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy e.g. alcohol withdrawal or brain damage); Parkinson's disease; narrow angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; phaeochromocytoma and patients who have shown hypersensitivity to thioxanthenes or other antipsychotics.

The elderly require close supervision because they are specially prone to experience such adverse effects as sedation, hypotension, confusion and temperature changes.

Recurrence of depressive symptoms on abrupt withdrawal is rare.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia have been described after abrupt cessation of thioxanthenes and similar drugs. The emergence of involuntary movement disorders (such as akathisia, dystonia and dyskinesia) has been reported. Therefore, gradual withdrawal is advisable.

Dependence has not been reported to date.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs.

It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which flupentixol is prescribed can also be associated with an increased risk of suicide-related events. In addition, these conditions may be co-morbid with major depressive disorder. The same precautions observed when treating patients with major depressive disorder should therefore be observed when treating patients with other psychiatric disorders.

Patients with a history of suicide-related events, or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment. A meta-analysis of placebo controlled clinical trials of antidepressant drugs in adult patients with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old.

Close supervision of patients and in particular those at high risk should accompany drug therapy especially in early treatment and following dose changes. Patients (and caregivers of patients) should be alerted about the need to monitor for any clinical worsening, suicidal behaviour or thoughts and unusual changes in behaviour and to seek medical advice immediately if these symptoms present.

As described for other psychotropics flupentixol may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients.

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.

Flupentixol should be used with caution in patients with risk factors for stroke.

As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol may cause QT prolongation. Persistently prolonged QT intervals may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in susceptible individuals (with hypokalemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorders, e.g. QT prolongation, significant bradycardia (<50 beats per minute), a recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmia.

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 Fluanxol and preventive measures undertaken.

Concomitant treatment with other antipsychotics should be avoided (see section 4.5).

The possibility of development of neuroleptic malignant syndrome (hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system) exists with any neuroleptic. The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation, and opiate and alcohol abuse are overrepresented among fatal cases.

Treatment: Discontinuation of the neuroleptic. Symptomatic treatment and use of general supportive measures. Dantrolene and bromocriptine may be helpful.Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the drug.

Blood dyscrasias, including thrombocytopenia, have been reported rarely. Blood counts should be carried out if a patient develops signs of persistent infection.

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.

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

Excipients

The tablets contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not receive this medicine.

The tablets also contain sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

In common with other similar drugs, flupentixol enhances the response to alcohol, the effects of barbiturates and other CNS depressants. Flupentixol may potentiate the effects of general anaesthetics and anticoagulants and prolong the action of neuromuscular blocking agents.

The anticholinergic effects of atropine or other drugs with anticholinergic properties may be increased. Concomitant use of drugs such as metoclopramide, piperazine or antiparkinson drugs may increase the risk of extrapyramidal effects such as tardive dyskinesia. Combined use of antipsychotics and lithium or sibutramine has been associated with an increased risk of neurotoxicity.

Antipsychotics may enhance the cardiac depressant effects of quinidine; the absorption of corticosteroids and digoxin. The hypotensive effect of vasodilator antihypertensive agents such as hydralazine and α-blockers (e.g. doxazosin), or methyl-dopa may be enhanced.

Increases in the QT interval related to antipsychotic treatment may be exacerbated by the co-administration of other drugs known to significantly increase the QT interval. Co-administration of such drugs should be avoided.

Relevant classes include:

• class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide)

• some antipsychotics (e.g. thioridazine)

• some macrolides (e.g. erythromycin)

• some antihistamines

• some quinolone antibiotics (e.g. moxifloxacin)

The above list is not exhaustive and other individual drugs known to significantly increase QT interval (e.g. cisapride, lithium) should be avoided.

Drugs known to cause electrolyte disturbances such as thiazide diuretics (hypokalaemia) and drugs known to increase the plasma concentration of flupentixol should also be used with caution as they may increase the risk of QT prolongation and malignant arrythmias (see section 4.4).

Antipsychotics may antagonise the effects of adrenaline and other sympathomimetic agents, and reverse the antihypertensive effects of guanethidine, possibly clonidine and similar adrenergic-blocking agents. Antipsychotics may also impair the effect of levodopa, adrenergic drugs and anticonvulsants.

The metabolism of tricyclic antidepressants may be inhibited and the control of diabetes may be impaired.

Pregnancy

As the safety of Fluanxol in human pregnancy has not been established, use during pregnancy, especially the first and last trimesters, should be avoided, unless the expected benefit to the patient outweighs the potential risk to the foetus.

The newborn of mothers treated with antipsychotics in late pregnancy, or labour, may show signs of intoxication such as lethargy, tremor and hyperexcitability, and have a low Apgar score.

Neonates exposed to antipsychotics (including Fluanxol) 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.

Breast-feeding

Flupentixol is excreted into the breast milk. If the use of Fluanxol is considered essential, nursing mothers should be advised to stop breast-feeding.

Alertness may be impaired, especially at the start of treatment, or following the consumption of alcohol; patients should be warned of this risk and advised not to drive or operate machinery until their susceptibility is known. Patients should not drive if they have blurred vision.

Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or early after treatment discontinuation (see section 4.4).

Undesirable effects are for the majority dose dependent. The frequency and severity are most pronounced in the early phase of treatment and decline during continued treatment.

Extrapyramidal reactions may occur, especially in the early phase of treatment. In most cases these side effects can be satisfactorily controlled by reduction of dosage and/or use of antiparkinsonian drugs. The routine prophylactic use of antiparkinsonian drugs is not recommended.

Antiparkinsonian drugs do not alleviate tardive dyskinesia and may aggravate them. Reduction in dosage or, if possible, discontinuation of flupentixol therapy is recommended. In persistent akathisia a benzodiazepine or propranolol may be useful.

¹ For injectable flupentixol presentations.

As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT prolongation, ventricular arrhythmias - ventricular fibrillation, ventricular tachycardia, Torsade de Pointes and sudden unexplained death have been reported for flupentixol (see section 4.4).

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

Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most common symptoms are nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgias, paraesthesias, insomnia, restlessness, anxiety, and agitation. Patients may also experience vertigo, alternate feelings of warmth and coldness, and tremor. Symptoms generally begin within 1 to 4 days of withdrawal and abate within 7 to 14 days.

Overdosage may cause somnolence, or even coma, extrapyramidal symptoms, convulsions, hypotension, shock, hyper-or hypothermia. ECG changes, QT prolongation, Torsade de Pointes, cardiac arrest and ventricular arrhythmias have been reported when administered in overdose together with drugs known to affect the heart.

Treatment is symptomatic and supportive, with measures aimed at supporting the respiratory and cardiovascular systems. The following specific measures may be employed if required.

• anticholinergic antiparkinson drugs if extrapyramidal symptoms occur.

• sedation (with benzodiazepines) in the unlikely event of agitation or excitement or convulsions.

• noradrenaline in saline intravenous drip if the patient is in shock. Adrenaline must not be given.

• Gastric lavage should be considered.

The precise pharmacological mode of action of flupentixol has not been determined. It has been postulated that at low dosage flupentixol binds to presynaptic dopamine receptors causing increased neurotransmitter release.

There is evidence that postsynaptic aminergic receptors become down regulated in response to increased levels of neurotransmitter and this is responsible for the observed improvement in depressive symptoms.

Mean oral bioavailability is about 55%. Maximum drug serum concentrations occur about 4 hours after dosing and the biological half-life is about 35 hours.

Flupentixol is widely distributed in the body. Metabolism is by sulphoxidation, N-dealkylation and glucuronic acid conjugation. Excretion is via the urine and faeces.

Nil of relevance

Lactose monohydrate

Potato starch

Talc

Magnesium stearate

Gelatin

Sucrose

Yellow iron oxide (E 172)

Beeswax

White wax

Carnauba wax.

None known.

Fluanxol tablets are stable for 2 years. The box is labelled with an expiry date.

Do not store above 25°C.

PVC/PVdC blister strips of 60 tablets per box.

Nil.

Lundbeck Ltd

Lundbeck House

Caldecotte Lake Business Park

Caldecotte

Milton Keynes

MK7 8LF

7 January 2012

POM