SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Fluanxol 0.5 mg film-coated tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each film-coated tablet contains 0.5 mg flupentixol (as 0.5840 mg flupentixol dihydrochloride)

Excipients with known effect:

Lactose monohydrate

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet

Round, slightly biconvex, yellow, film-coated tablet marked FD.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

Symptomatic treatment of depression (with or without anxiety).

4.2    Posology and method of administration

Posology

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.

Older patients

Older 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

Flupentixol is not recommended for use in children due to lack of clinical experience.

Patients with 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).

Patients with 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 If no effect has been observed within one week at maximum dosage the drug should be withdrawn.

Method of administration

The tablets are swallowed with water.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in 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.

4.4 Special warnings and precautions for use

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.

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.

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.

Older People

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

Cerebrovascular

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.

Increased Mortality in Older People with Dementia Data from two large observational studies showed that older 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 glucose-galactose malabsorption should not receive this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

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 a-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.

4.6 Fertility, pregnancy and lactation

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.

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.

Animal studies have shown reproductive toxicity (see section 5.3).

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.

Fertility

In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, libido decreased, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may have a negative impact on female and/or male sexual function and fertility.

If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation.

In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8 Undesirable effects

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

Blood and lymphatic system disorders	Thrombocytopenia, neutropenia, leukopenia, agranulocytosis
Immune system disorders	Hypersensitivity, anaphylactic reaction.
Endocrine disorder	Hyperprolactinaemia.
Metabolism and nutrition disorders	Increased appetite, weight increased. Decreased appetite. Hyperglycaemia, glucose tolerance abnormal.
Psychiatric disorders	Insomnia, depression, nervousness, agitation, libido decreased. Confusional state.

Nervous system disorders	Somnolence, akathisia, hyperkinesia, hypokinesia. Tremor, dystonia, dizziness, headache, disturbance in attention. Tardive dyskinesia, dyskinesia, parkinsonism, speech disorder, convulsion. Neuroleptic malignant syndrome.
Eye disorders	Accommodation disorder, vision abnormal. Oculogyration.
Cardiac disorders	Tachycardia, palpitations. Electrocardiogram QT prolonged.
Vascular disorders	Hypotension, hot flush.
Respiratory, thoracic and mediastinal disorders	Dyspnoea.
Gastrointestinal disorders	Dry mouth. Salivary hypersecretion, constipation, vomiting, dyspepsia, diarrhoea. Abdominal pain, nausea, flatulence.
Hepatobiliary disorders	Liver function test abnormal. Jaundice
Skin and subcutaneous tissuedisorders	Hyperhidrosis, pruritus. Rash, photosensitivity reaction, dermatitis.
Musculoskeletal and connective tissue disorder	Myalgia. Muscle rigidity.
Renal and urinary disorders	Micturition disorder, urinary retention.
Pregnancy, puerperium and perinatal conditions	Drug withdrawal syndrome neonatal (see 4.6).
Reproductive system and breast disorders	Ejaculation failure, erectile dysfunction. Gynaecomastia, galactorrhoea, amenorrhoea.

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.

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

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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Neuroleptics (antipsychotics), ATC code: N05AF01

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.

5.2. Pharmacokinetic Properties

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.

5.3    Preclinical safety data

Reproductive toxicity

In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Animal reproduction studies in mice, rats and rabbits have not shown evidence of teratogenic effects. Embryotoxic effects in terms of increased post implantation loss/increased absorption rates or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity.

6    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Betadex

Lactose monohydrate Maize starch Hydroxypropylcellulose Microcrystalline cellulose Croscarmellose sodium Talc

Vegetable oil, hydrogenated Magnesium stearate

Coating and colour:

Polyvinyl alcohol, partly hydrolyzed Titanium dioxide (E171) Macrogol/PEG 3350 Talc

Iron oxide yellow (E172) Macrogol/PEG6000

6.2. Incompatibilities

None known.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

PVC/PE/PVdC/Aluminium blister, pack with an outer carton; 60 tablets.

6.6 Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Lundbeck Limited Building K1 Timbold Drive Kents Hill Milton Keynes MK7 6BZ United Kingdom

PL 0458/0011R

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23 November 1982 / 17 March 2002

10 DATE OF REVISION OF THE TEXT

12/05/2015