Depression involving anxiety, asthenia and lack of initiative.

Chronic neuroses with anxiety, depression, and inactivity.
Psychosomatic disorders with asthenic reactions.
Schizophrenia and allied psychoses, especially with symptoms such as hallucinations, delusions and
thought disturbances along with apathy, lack of energy, lowered mood and withdrawal.

Posology
Adults
Depression. Depressive neuroses. Psychosomatic disorders.
Initially 1 mg daily as a single morning dose or 0.5 mg twice daily.
After one week the dosage may be increased to 2 mg daily 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.
Older patients
Older patients should receive half the recommended dosages, i.e. 0.5-1.5 mg daily.
Patients often respond to flupentixol within two or three days. If no effect has been observed within
one week of maximum dosage the drug should be withdrawn.
Adults
Schizophrenia and allied psychoses
Dosage should be individually adjusted according to the patient's condition. In general, small doses
should be used initially and increased to the optimal effective level as rapidly as possible based on the
therapeutic response. The maintenance dose can usually be given as a single morning dose.
Initially 3-15 mg/day divided in two or three daily doses, increased, if necessary, to 40 mg/day.
Maintenance dose usually is 5-20 mg/day.
Older patients
Older patients usually should receive dosages in the lower end of the dosage range.
Reduced renal function
Flupentixol can be given in usual doses to patients with reduced renal function.
Reduced liver function
Careful dosing and, if possible, a serum level determination is advisable.
Children
Flupentixol is not recommended for use in children due to lack of clinical experience.
Method of administration
The tablets are swallowed with water.
 

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 over-represented 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.
Like other neuroleptics flupentixol should be used with caution in patients with organic brain
syndrome, convulsion and advanced hepatic disease.
Not recommended for excitable or overactive patients in doses up to 25 mg/day since its activating
effect may lead to exaggeration of these characteristics. If previously the patient has been treated with
tranquillizers or neuroleptics with sedative effect, these should be withdrawn gradually.
As described for other psychotropics flupentixol may modify insulin and glucose responses calling for
adjustment of the antidiabetic therapy in diabetic patients.
Patients on long-term therapy, particularly on high doses, should be monitored carefully and evaluated
periodically to decide whether the maintenance dosage can be lowered.
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. Concomitant treatment with other antipsychotics
should be avoided (see section 4.5).

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.
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 flupentixol and
preventive measures undertaken

Older peolple
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.
Flupentixol 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. 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.

Combinations requiring precautions for use
Flupentixol may enhance the sedative effect of alcohol and the effects of barbiturates and other CNS
depressants.
Neuroleptics may increase or reduce the effect of antihypertensive drugs; the antihypertensive effect
of guanethidine and similar acting compounds is reduced.
Concomitant use of neuroleptics and lithium increases the risk of neurotoxicity.
Tricyclic antidepressants and neuroleptics mutually inhibit the metabolism of each other.
Flupentixol may reduce the effect of levodopa and the effect of adrenergic drugs.
Concomitant use of metoclopramide and piperazine increases the risk of extrapyramidal disorder.
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 (e.g. terfenadine, astemizole)
 some quinolone antibiotics (e.g. gatifloxacin, 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 thiazidediuretica (hypokalemia) 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).

Pregnancy
Flupentixol should not be administered during pregnancy unless the expected benefit to the patient
outweighs the theoretical risk to the foetus.
Neonates exposed to antipsychotics (including flupentixol) 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
As flupentixol is found in breast milk in low concentrations it is not likely to affect the infant when
therapeutic doses are used. The dose ingested by the infant is less than 0.5% of the weight related
maternal daily dose. Breast-feeding can be continued during flupentixol therapy if considered of
clinical importance but observation of the infant is recommended, particularly in the first 4 weeks after
giving birth.
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.
Effects were seen at doses well in excess of those applied during clinical use.

Fluanxol is a non-sedating drug in the low-moderate dosage range.
However, patients who are prescribed psychotropic medication may be expected to have some
impairment in general attention and concentration and should be cautioned about their ability to drive
or operate machinery.

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.
Frequencies are taken from the literature and spontaneous reporting. Frequencies are defined
as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000
to <1/1,000), very rare (<1/10,000), or not known (can not be estimated from the available data).

*)Cases of suicidal ideation and suicidal behaviours have been reported during flupentixol therapy or
early after treatment discontinuation (see section 4.4).
As with other drugs belonging to the therapeutic class of antipsychotics, rare cases of QT
prolongation, ventricular arrythmias - ventricular fibrillation, ventricular tachycardia, Torsade de
Pointes and sudden unexplained death have been reported for flupentixol (see section 4.4).
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 national reporting system (to
becompletednationally).

Symptoms:
Somnolence, coma, movement disorder, convulsions, shock, hyperthermia/hypothermia.

The highest orally administered single dose in clinical trials was 80 mg, and up to 320 mg/day has been
given.
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:
Treatment is symptomatic and supportive. Gastric lavage should be carried out as soon as possible
after oral ingestion and activated charcoal may be administered. Measures to support the respiratory
and cardiovascular systems should be instituted. Epinephrine (adrenaline) should not be used as
further lowering of blood pressure may result. Convulsions may be treated with diazepam and
extrapyramidal symptoms with biperiden.

Pharmacotherapeuticgroup
Neuroleptics (antipsychotics), ATC-code: N 05 AF 01
Mechanism of action
Flupentixol is a neuroleptic of the thioxanthene group.
Flupentixol is a mixture of two geometric isomers, the active flupentixol and trans(E)-flupentixol,
approximately in the ratio of 1:1.
The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking effect but possibly
also 5-HT (5-hydroxytryptamine) receptor blockade contributes. In vitro and in vivo flupentixol has high
affinity for both dopamine D1 and D2 receptors whereas fluphenazine is almost D2 selective in vivo. The
atypical antipsychotic, clozapine, shows - as flupentixol - equiaffinity to D1 and D2 receptors both in vitro
and in vivo.
Flupentixol has high affinity for α1-adrenoceptors and 5-HT2 receptors, although lower than that of
chlorprothixene, high-dose phenothiazines and clozapine, but no affinity for cholinergic muscarine
receptors. It has only slight antihistaminergic properties and no α2-adrenoceptor blocking activity.
Flupentixol has proven to be a potent neuroleptic in all the behavioural studies for neuroleptic (dopamine
receptor blocking) activity. Correlation is found in the in vivo test models, the affinity for dopamine D2
binding sites in vitro and the average, daily oral antipsychotic doses.
Perioral movements in rats are dependent on D1 receptor stimulation or blockade of the D2 receptor
population. The movements can be prevented by flupentixol. Likewise, the results from investigations in
monkeys indicate that oral hyperkinesia is more related to D1 receptor stimulation and to a less degree to
D2 receptor supersensitivity. This leads to the suggestion that D1 activation is responsible for similar
effects in man, i.e. dyskinesia. Therefore, blockade of D1 receptors should be advantageous.
Flupentixol prolongs alcohol- and barbiturate-induced sleeping time in mice in only very high doses
indicating a very weak sedative action in clinical use.
Like most other neuroleptics, flupentixol dose-dependently increases the serum prolactin level.
Clinical efficacy and safty
In clinical use flupentixol has a broad spectrum of activity that varies according to the dosage.

Flupentixol in low dosages (1-2 mg/day) has antidepressant, anxiolytic and activating effects.
In moderate dosages (3-25 mg/day) flupentixol is intended for the treatment of acute and chronic
psychoses. In this dosage range flupentixol has practically no unspecific sedative effect and is not
suited for patients with severe psychomotor agitation. Besides causing a significant reduction or
complete elimination of the nuclear symptoms of schizophrenia such as hallucinations, delusions and
thought disturbances flupentixol also has disinhibiting (antiautistic and activating) and mood-elevating
properties making flupentixol particularly useful in the treatment of apathetic, withdrawn, depressed
and poorly motivated patients.
The antipsychotic effect increases with increasing dosage; in addition some sedation should be
anticipated. Flupentixol has within the whole dosage range a pronounced anxiolytic effect and even in
high-dose treatment the mood elevating and disinhibiting effects of flupentixol are retained. High
dose treatment does not increase the frequency of extrapyramidal symptoms.

The following data concerns the active cis(Z)-isomer.
Absorption
Oral administration results in maximum serum levels in about 4-5 hours. Oral bioavailability is about
40 %.
Distribution
The apparent volume of distribution (Vd)β is about 14.1 l/kg. The plasma protein binding is about 99 %.
Biotransformation
The metabolism of flupentixol proceeds along three main routes - sulphoxidation, side chain Ndealkylation
and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological
activity. Flupentixol dominates over metabolites in brain and other tissues.
Elimination
The elimination half-life (T½ β) is about 35 hours and the mean systemic clearance (Cls) is about 0.29
l/min.
Flupentixol is excreted mainly with faeces, but also to some degree with the urine. When tritium
labelled flupentixol was administered to man the excretion pattern showed the excretion via faeces to
be about 4 times the urinary excretion.
In nursing mothers flupentixol is excreted in small amounts with the breast milk. The ratio milk
conc./serum conc. in women is on an average 1.3.
Linearity
The kinetics is linear. Steady state plasma levels are achieved in about 7 days. The mean minimum
steady state level corresponding to 5 mg flupentixol orally once-a-day was about 1.7 ng/ml (3.9
nmol/l).
Older patients
Pharmacokinetic investigations have not been done in older patients. However, for the related
thioxanthene drug, zuclopenthixol, the pharmacokinetic parameters are widely independent of the age
of the patients.

Reduced renal function
Based on the above characteristics for elimination it is reasonable to assume that reduced kidney
function is likely not to have much influence on the serum levels of parent drug.
Reduced hepatic function
No data available.
Pharmacokinetic / Pharmacodynamic relationship
A minimum (i.e. concentration measured just before administration of a dose) serum (plasma)
concentration of 1-3 ng/ml (2-8 nmol/l) is suggested as a guideline for maintenance treatment of
schizophrenic patients with a low-moderate degree of illness.

Acute toxicity
Flupentixol has low acute toxicity.
Chronic toxicity
In chronic toxicity studies there were no findings of concern for the therapeutic use of flupentixol.
Reproductive toxicity
In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Effects were
seen at doses well in excess of those applied during clinical use.
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.
Carcinogenicity
Flupentixol has no carcinogenic potential.

Tablet core:
Lactose monohydrate,
Potato starch,
Talc,
Gelatine,
Magnesium stearate.
Coating:
Gelatine,
Sucrose,
Sucrose powder.
Colour:
Yellow iron oxide (E 172)
Polishing wax: a mixture of white wax and carnauba wax.

Not applicable.

0.5 mg in blisters: “Do not store above 30ºC
3 mg in container: Do not store above 30ºC.

0.5 mg: 50, 60 and 100 in blisters, 30, 50 and 100 in container (Polypropylene or High Density
Polyethylene (HDPE))
1 mg: 60 and 100 in blisters, 50, 60 and 100 in container (Polypropylene or High Density
Polyethylene (HDPE))
3 mg: 50 and 100 in container (Polypropylene or High Density Polyethylene (HDPE))
5 mg: 50 and 100 in container (Polypropylene or High Density Polyethylene (HDPE))
The screw cap of HDPE containers is child-resistant
Not all strengths and pack sizes may be marketed.

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