With any antipsychotic, there is a possibility of developing a neuroleptic malignant syndrome with symptoms: hyperthermia, muscle rigidity, unstable consciousness, unstable functioning of the autonomic nervous system. This risk is however greater with more potent neuroleptics. Patients with pre-existing brain insufficiency, with mental retardation, and with opiate and alcohol abuse are overrepresented among the fatal cases.

Treatment: Discontinue neuroleptic therapy. Treatment is symptomatic and involves general supportive measures. Administration of dantrolene and bromocirptine may be helpful. Symptoms may persist for a week or longer after discontinuation of oral neuroleptics; somewhat longer when associated with depot forms of the drug.

Like other neuroleptics, flupentixol decanoate should be used with caution in patients with cerebral insufficiency, seizure disorders or with pronounced liver disease.

Flupentixol decanoate at low doses is not recommended for excited or “overactive” patients, as it may further exacerbate these characteristics.

As described with other psychotropic drugs, flupentixol decanoate may alter insulin and blood glucose levels, requiring adjustment of antidiabetic therapy in diabetics.

During long-term treatment, especially at high doses, it is advisable to closely monitor the patient and evaluate periodically with a view to reducing the maintenance dose.

As with other drugs belonging to the therapeutic class of antipsychotics, flupentixol decanoate may cause QT prolongation. Persistent QT interval prolongation may increase the risk of malignant arrhythmias. Therefore, flupentixol decanoate should be used with caution in susceptible individuals (hypokalaemia, hypomagnesia or genetic predisposition) and in patients with a history of cardiovascular disorder, e.g. QT prolongation, significant bradycardia (< 50 beats per minute), recent acute myocardial infarction, uncompensated heart failure, or cardiac arrhythmias. In addition, flupentixol should be used with caution in patients with a family history of QT prolongation. Concomitant treatment with other antipsychotics should be avoided (see section 4.5).

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. Because improvement may not be seen during the first few weeks or more of treatment, patients should be closely monitored until 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 Fluanxol Depot is prescribed may also be associated with an increased risk of suicide-related events. In addition, these conditions may be comorbid with major depressive disorder. Therefore, the same precautions that apply to patients with major depressive disorder should be observed for patients with other psychiatric conditions.

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 adults with psychiatric disorders showed an increased risk of suicidal behaviour with antidepressants compared to placebo in patients less than 25 years old. These patients, and in particular those at high risk, should receive close monitoring during treatment, particularly 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.

Some cases of venous thromboembolism (VTE) have been reported with antipsychotics. 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 Depot and preventive measures undertaken.

Leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including flupentixol decanoate.
Long-acting depot antipsychotics should be used with caution in combination with other drugs known to have myelosuppressive potential, as these may not be rapidly cleared from the body in cases where this might be necessary.

Elderly

Cerebrovascular
In randomised placebo controlled clinical trials in a dementia population, a three-fold increased risk of cerebrovascular adverse events has been seen with some atypical antipsychotics. The mechanism for this increased risk is unknown. An increased risk cannot be excluded with other antipsychotics or in other patient populations. Flupentixol decanoate should be used with caution in patients with risk factors for cerebral vascular accident (CVA).

Increased mortality in older people with dementia
Data from two large observational studies suggest a slightly increased risk of mortality in older people with dementia treated with antipsychotics compared to older people who do not receive treatment. At present, there are insufficient data to accurately estimate the precise magnitude of the risk. The cause of the increased risk is still unknown.

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

Combinations requiring caution in use
Flupentixol decanoate may enhance the sedative effects of alcohol, barbiturates and other drugs that cause central nervous system depression.

Neuroleptics may enhance or antagonize the blood pressure lowering effect of antihypertensives; the antihypertensive effect of guanfacine and similar substances is antagonized.
Concomitant use of neuroleptics and lithium increases the risk of neurotoxicity. Tricyclic antidepressants and neuroleptics may inhibit each other's metabolism.
Flupentixol decanoate may reduce the effect of levodopa and adrenergic agents.
Concomitant use of metoclopramide or piperazine increases the risk of extrapyramidal disorder.

In association with antipsychotic treatment, QT interval prolongation may be exacerbated by concomitant administration of other drugs known to significantly prolong the QT interval. Concomitant administration of such drugs should be avoided.
Classes of drugs involved include:

• Class Ia and III antiarrhythmic drugs (e.g. quinidine, amiodarone, sotalol, dofetilide)
• Some antipsychotics (e.g. thioridazide)
• Some macrolides (e.g. erythromycin)
• Some antihistamines (e.g. terfenadine, astemizole)
• Some quinolone antibiotics (e.g. gatifloxacin, moxifloxacin)

This list is not exhaustive and other specific drugs known to significantly prolong the QT interval (e.g. cisapride, lithium) should be avoided.

Flupentixol should be used with caution with medicinal products known to cause electrolyte imbalance such as thiazide diuretics (hypokalaemia) and with medicinal products known to increase the plasma concentration of flupentixol decanoate, as these may increase the risk of QT prolongation and malignant arrhythmias (see section 4.4).

Pregnancy
Fluanxol decanoate should only be administered during pregnancy if the therapeutic benefit to the patient is greater than the theoretical risk to the fetus.

Newborns born to mothers treated with neuroleptics at the end of pregnancy or during labour may show signs of intoxication such as lethargy, tremor and hyperexcitability and have a lower Apgar score.

Neonates exposed to antipsychotics (including flupentixol decanoate) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or discontinuation symptoms that may vary in severity and duration following delivery. Agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Consequently, neonates should be monitored carefully.

Studies in animals have shown reproductive toxicity (see section 5.3).

Breastfeeding
Given the low concentrations of flupentixol found in breast milk, it is unlikely that, at therapeutic doses, it will affect the infant. The dose ingested by the neonate is less than 0.5% of the daily dose ingested by the mother (in mg/kg). If clinical importance prevails, breast-feeding may be continued during flupentixol decanoate therapy, but observation of the neonate, especially during the first 4 weeks after birth, is recommended.

Fertility
There are no clinical trial data available on the effect of the active substance flupentixol on fertility.

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

If clinically significant hyperprolactinemia, galactorrhoea, amenorrhea or sexual dysfunction occur, a dose reduction (if possible) or discontinuation of therapy should be considered. The adverse effects are reversible upon discontinuation of therapy.

In preclinical fertility studies in rats, flupentixol slightly affected the pregnancy rate in female rats. The effects were seen at doses well above those used clinically.

Flupentixol decanoate in low to moderate doses (up to 100 mg every 2 weeks) is not sedating which may have minor to moderate influence on the ability to drive and use machines.
However, patients prescribed psychotropic drugs may be expected to have minor impairment of general attention and concentration. Therefore, caution is advised when driving or using machines.

Given the form of administration, it is unlikely that overdose symptoms will occur.

Symptoms
Drowsiness, coma, movement disorders, convulsions, shock, hyperthermia or hypothermia.
When taken in overdose with drugs known to affect the heart, ECG changes, QT prolongation, Torsades de Pointes, cardiac arrest and ventricular arrhythmias have been reported.

Treatment
Treatment is symptomatic and supportive. Measures should be taken to support the respiratory and cardiovascular systems. Epinephrine (adrenaline) will not be administered, as further reduction in blood pressure may occur. Convulsions can be treated with diazepam and extrapyramidal symptoms with biperiden.

Pharmacotherapeutic group: neuroleptics (antipsychotics); ATC code: N05AF01.

Mechanism of action
Flupentixol is a neuroleptic belonging to the thioxanthenes group.
The antipsychotic effect of a neuroleptic is linked to the antagonism of dopaminergic receptors, but 5-HT (5-hydroxidetryptamine) receptor blockade may also play a role. In vitro and in vivo, flupentixol has a high affinity for both dopamine D ₁ and D ₂ receptors, while fluphenazine is almost D ₂ selective in vivo . The atypical antipsychotic, clozapine, shows – like flupentixol – a similar affinity for D ₁ and D ₂ receptors, both in vitro and in vivo .

Flupentixol has a high affinity for α ₁ -adrenoceptors and 5-HT _{2 receptors (but lower than that of chlorprothixene, high doses of phenothizines and clozapine), but no affinity for cholinergic muscarinic receptors. It has only mild antihistaminic properties and no α 2} -adrenoceptor blockade activity.

Flupentixol was found to be a potent neuroleptic in all behavioural studies on neuroleptic action (dopamine receptor blockade). Correlation was found in in vivo test models, the affinity for dopamine D ₂ binding sites in vitro and the average daily oral antipsychotic doses.
Perioral movements in rats are dependent on D ₁ receptor stimulation or blockade of the D ₂ receptor population. The movements can be prevented by flupentixol. Similarly, results from monkey studies show that oral hyperkinesia is more related to D ₁ receptor stimulation and to a lesser extent to D ₂ receptor hypersensitivity. This leads to the assumption that D ₁ activation is responsible for similar effects in humans, e.g. dyskinesia. Therefore, blockade of D ₁ receptors might be of benefit.

Like most neuroleptics, flupentixol increases serum prolactin levels in a dose-dependent manner.

Pharmacological studies have clearly shown that the oil solution of flupentixol decanoate has a prolonged neuroleptic effect and that the amount of drug required to maintain a certain effect over a longer period is considerably less with the depot preparations than with daily oral administration of flupentixol. Only at very high doses could a very moderate and short-lived potentiation of the duration of sleep induced by barbiturates be demonstrated in mice. Hence it is unlikely that any significant interference with anaesthetics could occur in patients receiving depot drugs.

Clinical efficacy and safety
In clinical use, flupentixol decanoate is indicated for maintenance treatment of chronically psychotic patients. The antipsychotic effect increases with increasing dose. Flupentixol decanoate is non-sedating at low to moderate doses (up to 100 mg/2 weeks), whereas some non-specific sedation may be expected when higher doses are administered.
Flupentixol decanoate is particularly useful for the treatment of apathetic, withdrawn, depressed and poorly motivated patients.
Flupentixol decanoate allows uninterrupted treatment, especially for those patients who are not reliable in taking their prescribed oral medication.
Flupentixol decanoate thus prevents frequent relapses for patients who are not compliant with oral medication.

Pediatric patients
No data available

Absorption
By esterifying flupentixol with decanoic acid, a highly lipophilic substance is obtained, flupentixol decanoate. Dissolved in vegetable oil and injected intramuscularly, this substance diffuses rather slowly into the interstitial fluid where it is enzymatically hydrolysed and the active substance flupentixol is released.

Peak serum concentrations are generally reached after a period of 3 to 7 days after intramuscular injection. The half-life is estimated at 3 weeks (which reflects the release from the depot); steady-state conditions are reached after approximately 3 months on repeated administration.

Distribution
The fictitious volume of distribution (V _d ) _β is approximately 14.1 l/kg. Serum protein binding is approximately 99%.

Biotransformation
Flupentixol metabolism follows three main pathways: sulfoxidation, N-dealkylation of the lateral chain, and glucuronidation. The metabolites have no pharmacological activity. Flupentixol is present in higher abundance than its metabolites in the brain and other tissues.

Elimination
The elimination half-life (T _{½ β} ) of flupentixol is approximately 35 hours and the mean systemic clearance (Cl _s ) is approximately 0.29 l/min.
Flupentixol is excreted mainly in the faeces, but also to some extent in the urine. In humans, after administration of tritium-labelled flupentixol, faecal excretion was 4 times that in urine.
Flupentixol is excreted in breast milk in small quantities. The ratio of milk to serum concentrations averages 1.3.

Linearity
The kinetics are linear. The mean steady-state serum level of flupentixol for injection corresponding to a dose of 40 mg flupentixol decanoate every 2 weeks is approximately 6 nmol/l.

Elderly
Pharmacokinetic studies have not been performed in elderly. For the similar drug belonging to the thioxanthene group, zuclopenthixol, the pharmacokinetic parameters are largely independent of the age of the patient.

Impaired renal function
Based on the above features of elimination, it is reasonable to assume that impaired renal function is unlikely to have much influence on the serum levels of the parent drug.

Reduced liver function
No data available

Pharmacokinetic/pharmacodynamic relationship
A pre-injection plasma concentration of 1-3 ng/ml (2-8 nmol/l) and a max./min. fluctuation < 2.5 have been suggested as a guideline for maintenance treatment in patients with mild to moderate schizophrenia. Pharmacokinetically, a dose of 40 mg/2 weeks of flupentixol decanoate is equivalent to a daily oral dose of 10 mg flupentixol.

Pediatric patients
No data available

Acute toxicity
Flupentixol has weak acute toxicity.

Chronic toxicity
In chronic toxicity studies there were no concerning findings for the therapeutic use of flupentixol.

Reproductive toxicity
In fertility studies in rats, flupentixol slightly affected the pregnancy rate in female rats. The effects were seen at doses well above those used clinically.

Reproductive studies in mice, rats and rabbits have not shown a teratogenic effect. Embryotoxic effects in terms of increased post-implantation loss/increased absorption rate or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity.

Carcinogenicity
Flupentixol has no carcinogenic potential.

Local toxicity
Local tolerance is good. Local muscle damage was observed after injection of neuroleptics in aqueous solutions. After intramuscular injection of flupentixol decanoate oil solution in rabbits, only slight haemorrhage and oedema were observed.

Medium chain, saturated triglycerides.

Do not mix flupentixol decanoate with other depot preparations containing sesame oil as a vehicle, as this will drastically alter the pharmacokinetic properties of the preparations involved.

4 years

Store in the original package in order to protect from light.

20 mg/ml:
Colourless glass (type I glass) ampoules of 1 ml.
Boxes of 1 x 1 ml, 10 x 1 ml
100 mg/ml:
Colourless glass (type I glass) ampoules of 1 ml.
Boxes of 1 x 1 ml or 10 x 1 ml

Not all pack sizes may be marketed.

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

Date of first grant of the permit :

Fluanxol 20 mg/ml solution for injection  : 01/04/1971
Fluanxol 100 mg/ml solution for injection  : 01/02/1976

Date of last renewal      : 19/01/2007