FLUANXOL LP 100 mg/1 ml Injectable solution IM 1 ampoule/1ml

Solution for injection.
1 ml in ampoule (glass). Box of 1.

For one ampoule of 1 ml:

Flupentixol decanoate: 100 mg

Excipients:

Long-term treatment of chronic psychotic states (schizophrenia, chronic non-schizophrenic delusional disorders: paranoid delusions, chronic hallucinatory psychoses).

Dosage

FLUANXOL LP 100 mg/1 ml, injectable solution (IM) will most often be used to relay oral neuroleptic treatment.

In adults

Dosage strictly individual according to the clinical picture:

• antipsychotic effect associated with a stimulating and disinhibiting effect without anxiogenic effect: from 20 to 80 mg every two weeks,
• antideliriant and anti-hallucinatory effect associated with a sedative effect: from 80 to 300 mg every 2 to 3 weeks.

In elderly subjects, epileptic patients

Dosage reduced to half or a quarter of the dosage mentioned above.

FLUANXOL LP 100 mg/1 ml, injectable solution (IM) is administered by deep intramuscular route into the upper outer quadrant of the gluteal muscle.

Do not use the intravenous route.

The use of glass syringes is recommended due to the oily excipient.

The injection rhythm is, in general, every 14 days.

When switching from the oral route to the injectable route, the dose of FLUANXOL LP 100 mg/1 ml, injectable solution (IM) to be injected will be between two-thirds and the entire daily dosage of FLUANXOL 4 PERCENT, oral solution, drops.

Method of administration

Intramuscular route.

This medicine is contraindicated in the following situations:

• Hypersensitivity to the active substance or to any of the excipients listed in section Composition,
• risk of angle-closure glaucoma,
• risk of urinary retention related to urethro-prostatic disorders,
• disturbances of consciousness whatever the cause (for example alcohol, barbiturate or opiate intoxication), coma,
• in association with a non-Parkinson dopaminergic agent (cabergoline, quinagolide), citalopram, escitalopram, hydroxyzine, domperidone, piperaquine (see section Interactions).

In case of unexplained hyperthermia, it is imperative to suspend treatment, as this sign may be one of the elements of the malignant syndrome described with neuroleptics (pallor, hyperthermia, autonomic disorders, altered consciousness, muscular rigidity).

Signs of autonomic dysfunction, such as sweating and arterial instability, may precede the onset of hyperthermia and therefore constitute early warning signs.

Although this effect of neuroleptics may be idiosyncratic in origin, certain risk factors appear to predispose to it, such as dehydration or organic brain damage.

Symptoms may persist for more than one week after discontinuation of oral neuroleptics, and slightly longer when they are associated with the LP forms of these medicinal products.

Monitoring may be advised in epileptic patients and subjects with other predisposing factors (cerebral impairment) due to the possibility of lowering the epileptogenic threshold.

Flupentixol is not recommended in agitated or deluded patients at doses up to 25 mg/day, as its stimulating effect may lead to an exacerbation of these characteristics. If the patient has previously been treated with tranquillisers or neuroleptics with a sedative effect, they should be discontinued gradually.

Flupentixol should also be used with caution:

• in elderly subjects because of their marked sensitivity (sedation and hypotension),
• in patients with severe cardiovascular disease, due to haemodynamic changes, in particular hypotension,
• in patients with renal or hepatic impairment, due to the risk of overdose,
• in patients with Parkinson's disease who absolutely require neuroleptic treatment.

Prolongation of the QT interval

Flupentixol may cause prolongation of the QT interval. This effect, known to potentiate the risk of occurrence of serious ventricular rhythm disorders, in particular of the torsades de pointes type, is increased by the presence of bradycardia, hypokalaemia, congenital or acquired long QT (association with a medicinal product increasing the QT interval) (see section Adverse effects).

Therefore, when the clinical situation permits, it is advisable to ensure before any administration that there are no factors that may favour the occurrence of this arrhythmia:

• bradycardia below 55 beats per minute,
• hypokalaemia,
• congenital prolongation of the QT interval,
• current treatment with a medicinal product likely to cause marked bradycardia (< 55 beats per minute), hypokalaemia, slowing of intracardiac conduction, prolongation of the QT interval (see section Interactions).

Except in emergency situations, it is recommended to perform an ECG as part of the initial assessment of patients who are to be treated long-term with a neuroleptic.

Cases of hyperglycaemia or glucose intolerance and the occurrence or exacerbation of diabetes have been reported in patients treated with antipsychotics (see section Adverse effects).

Patients treated with FLUANXOL must undergo clinical and biological monitoring in accordance with current recommendations on cardiometabolic follow-up. Particular attention is recommended for diabetic patients or those with risk factors for diabetes, and the antidiabetic treatment should be adjusted if necessary.

Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patients treated with antipsychotics often have acquired risk factors for VTE, all risk factors for the occurrence of VTE should be identified before and during treatment with FLUANXOL, and preventive measures should be taken where appropriate.

Cases of leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including flupentixol decanoate.

Long-acting antipsychotics should be used with caution when combined with other medicines known to have a myelosuppressive potential, because these cannot be rapidly eliminated by the body.

Elderly

Cerebrovascular accident

In randomised placebo-controlled clinical studies conducted in elderly patients with dementia treated with certain atypical antipsychotics, a higher risk of cerebrovascular accident compared with placebo was observed. The mechanism of such an increased risk is not known. An increased risk with other antipsychotics or in other patient populations cannot be excluded. This medicinal product should be used with caution in patients with risk factors for cerebrovascular accident.

Increased mortality in elderly patients with dementia

The results of two observational studies conducted in a large number of patients showed that elderly patients with dementia treated with antipsychotics present a slight increase in the risk of mortality compared with those not treated. The available data are insufficient to establish a precise estimate of this risk, and the cause of this increase is unknown.

FLUANXOL is not indicated for the treatment of behavioural disturbances associated with dementia.

Sedative medicinal products

It must be taken into account that many medicines or substances can add together their central nervous system depressant effects and contribute to reduced alertness. These include morphine derivatives (analgesics, antitussives and substitution treatments), neuroleptics, barbiturates, benzodiazepines, anxiolytics other than benzodiazepines (for example, meprobamate), hypnotics, sedative antidepressants (amitriptyline, doxepin, mianserin, mirtazapine, trimipramine), sedating H1 antihistamines, centrally acting antihypertensives, baclofen and thalidomide.

Medicinal products that may induce torsades de pointes

This serious cardiac rhythm disorder may be caused by a number of medicines, whether antiarrhythmic or not. Hypokalaemia (see potassium-lowering medicines) is a predisposing factor, as is bradycardia (see bradycardia-inducing medicines) or a pre-existing, congenital or acquired, prolongation of the QT interval.

The medicines responsible for this adverse effect include, in particular, class Ia and class III antiarrhythmics, and certain neuroleptics. Other molecules not belonging to these classes are also implicated.

For dolasetron, erythromycin, spiramycin and vincamine, only the forms administered intravenously are concerned by this interaction.

The use of a torsadogenic medicine with another torsadogenic medicine is generally contraindicated.

However, some of them, because of their essential nature, are exceptions to the rule, being only advised against with other torsadogenic medicines. These are methadone, antiparasitics (chloroquine, halofantrine, lumefantrine, pentamidine) and neuroleptics.

However, citalopram, escitalopram, domperidone, hydroxyzine and piperaquine do not follow this relaxation and are contraindicated with all torsadogenic medicines.

Atropinic medicinal products

It must be taken into account that atropine-like substances can add up their undesirable effects and more easily cause urinary retention, an acute attack of glaucoma, constipation, dry mouth, etc.

The various anticholinergic medicines are represented by imipramine-like antidepressants, most anticholinergic H1 antihistamines, anticholinergic antiparkinsonian agents, anticholinergic antispasmodics, disopyramide, phenothiazine neuroleptics as well as clozapine.

Medicines causing orthostatic hypotension

Besides antihypertensives, many medicines may cause orthostatic hypotension. This is notably the case for nitrates, phosphodiesterase type 5 inhibitors, alpha-blockers used in urology, imipramine-like antidepressants and phenothiazine neuroleptics, dopamine agonists and levodopa. Their concomitant use therefore risks increasing the frequency and intensity of this undesirable effect. Refer to the interactions specific to each class, with the corresponding levels of constraint.

Contraindicated combinations

+ Non-Parkinson dopaminergic agents (cabergoline, quinagolide)

Reciprocal antagonism between the dopamine agonist and neuroleptics.

+ Citalopram, escitalopram

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Hydroxyzine

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Domperidone

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Piperaquine

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Combinations not recommended

+ Alcohol (beverage or excipient)

Potentiation by alcohol of the sedative effect of neuroleptics.

Impaired alertness may make driving vehicles and using machines dangerous.

Avoid taking alcoholic beverages and medicines containing alcohol.

+ Levodopa

Reciprocal antagonism of levodopa and neuroleptics.

In parkinsonian patients, use the minimum effective doses of each of the two medicines.

+ Dopaminergic antiparkinsonian agents (amantadine, apomorphine, bromocriptine, entacapone, lisuride, pergolide, piribedil, pramipexole, rasagiline, ropinirole, rotigotine, selegiline, tolcapone)

Reciprocal antagonism between the dopamine agonist and neuroleptics.

The dopaminergic agent may cause or worsen psychotic disorders. If treatment with neuroleptics becomes necessary in a patient with Parkinson's disease treated with a dopaminergic agent, the latter must be gradually reduced until discontinued (abrupt discontinuation exposes the patient to a risk of "neuroleptic malignant syndrome").

+ Antiparasitic agents liable to cause torsade de pointes (chloroquine, halofantrine, lumefantrine, pentamidine)

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

If possible, interrupt one of the two treatments. If the combination cannot be avoided, prior QT check and monitored ECG surveillance.

+ Hydroxychloroquine

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Methadone

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Other neuroleptics that may cause torsades de pointes (amisulpride, chlorpromazine, cyamemazine, droperidol, fluphenazine, haloperidol, levomepromazine, pimozide, pipamperone, pipotiazine, sulpiride, sultopride, tiapride, zuclopenthixol)

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Other medicines that may cause torsades de pointes (amiodarone, arsenious acid, diphemanil, disopyramide, IV dolasetron, dronedarone, IV erythromycin, hydroquinidine, mequitazine, mizolastine, moxifloxacin, prucalopride, quinidine, sotalol, IV spiramycin, toremifene, vandetanib, IV vincamine)

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Sodium oxybate

Increased central depression. Impaired alertness may make driving vehicles and using machines dangerous.

Associations requiring precautions for use

+ Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol, nebivolol)

Vasodilator effect and risk of hypotension, particularly orthostatic (additive effect).
Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Clinical and electrocardiographic monitoring.

+ Bradycardic agents

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Clinical and electrocardiographic monitoring.

+ Hypokalaemia-inducing agents

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Correct any hypokalaemia before administering the product and carry out clinical, electrolyte and electrocardiographic monitoring.

+ Anagrelide

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Clinical and electrocardiographic monitoring during the combination.

+ Azithromycin, clarithromycin, roxithromycin

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Clinical and electrocardiographic monitoring during the combination.

+ Ciprofloxacin, levofloxacin, norfloxacin

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Clinical and electrocardiographic monitoring during the combination.

+ Ondansetron

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

+ Lithium

Risk of onset of neuropsychiatric signs suggestive of neuroleptic malignant syndrome or of lithium intoxication.

Regular clinical and biological monitoring, particularly at the start of the combination.

Associations to be taken into account

+ Medicines lowering blood pressure

Risk of increased hypotension, in particular orthostatic hypotension.

+ Other anticholinergic medicines

Additive atropine-like undesirable effects such as urinary retention, constipation, dry mouth...

+ Other sedative medicines

Increased central depression.

Impaired alertness may make driving vehicles and using machines dangerous.

+ Dapoxetine

Risk of increased adverse effects, notably dizziness or syncope.

+ Orlistat

Risk of therapeutic failure in case of concomitant treatment with orlistat.

Pregnancy

Animal studies have shown reproductive toxicity (see section Preclinical safety).

Maintaining good maternal psychological balance is desirable throughout pregnancy to avoid any decompensation. If drug treatment is necessary to ensure this balance, it must be initiated or continued at an effective dose throughout pregnancy.

Clinical data are insufficient to draw a conclusion.

It is preferable to avoid using FLUANXOL during pregnancy, whatever the term. If it proves essential to prescribe treatment with FLUANXOL during pregnancy, newborns must be closely monitored.

Indeed, newborns exposed to antipsychotics (including FLUANXOL) during the third trimester of pregnancy present a risk of adverse events including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration after birth. The following reactions have been reported: agitation, hypertonia, hypotonia, tremor, abnormal drowsiness, respiratory distress, feeding disorders.

Breast-feeding

Breastfeeding is not recommended during the duration of treatment.

Fertility

FLUANXOL may cause hyperprolactinaemia and disorders of reproductive function that may have an impact on female and/or male fertility (see section Adverse effects).

In preclinical studies in rats, flupentixol affected the pregnancy rate of females.

Attention is drawn, in particular to drivers of vehicles and users of machinery, to the risks of drowsiness associated with the use of this medicine.

The majority of adverse effects are dose-dependent. The frequency and severity of these effects are more pronounced at the start of treatment and subside thereafter.

Extrapyramidal effects may occur, especially at the beginning of treatment. In most cases, these adverse effects can be satisfactorily controlled by reducing the dose and/or administering anticholinergic antiparkinsonian agents.

The use of anticholinergic antiparkinsonian agents is not recommended as routine prophylaxis. Antiparkinsonian medicinal products have no action on tardive dyskinesia and may worsen it. It is recommended to reduce the dose or, where possible, discontinue treatment with flupentixol.

The frequencies of the adverse effects below are not determinable (cannot be estimated from the available data from clinical trials, literature data and spontaneous reports).

Blood and lymphatic system disorders	Leukopenia, neutropenia, agranulocytosis, thrombocytopenia.
Immune system disorders	Hypersensitivity, anaphylactic reaction.
Endocrine disorders	Hyperprolactinemia.
Metabolism and nutrition disorders	Increased or decreased appetite, weight gain, hyperglycaemia, glucose intolerance.
Psychiatric disorders	Confusion, decreased libido, insomnia, depression, agitation, nervousness.
Nervous system disorders	Headache, convulsion, akathisia, dyskinesia, tardive dyskinesia, dystonia, extrapyramidal syndrome or parkinsonism (such as tremor, hyperkinesia, hypokinesia), speech disorder, drowsiness, dizziness, neuroleptic malignant syndrome.
Eye disorders	Oculogyric crisis, accommodation disorder, visual disturbances.
Cardiac disorders	QT interval prolongation, cardiac arrest, unexplained sudden death, ventricular tachycardia, torsades de pointes.
Vascular disorders	Hypotension, venous thromboembolism (see section Warnings and precautions).
Respiratory, thoracic and mediastinal disorders	Dyspnoea.
Gastrointestinal disorders	Abdominal pain, nausea, vomiting, diarrhoea, constipation, hypersalivation, dry mouth.
Hepatobiliary disorders	Abnormal liver function tests, jaundice, hepatitis.
Skin and subcutaneous tissue disorders	Pruritus, hyperhidrosis, photosensitivity reaction, skin eruptions such as rash, erythema, bullous dermatitis.
Musculoskeletal and systemic disorders	Muscle rigidity, torticollis, trismus, myalgia.
Renal and urinary disorders	Urinary retention, micturition disorder.
Pregnancy, puerperal and perinatal conditions	Neonatal withdrawal syndrome (see section Fertility, pregnancy and breastfeeding).
Disorders of the reproductive system and breast	Gynaecomastia, galactorrhoea, ejaculation disorder, erection disorder, amenorrhoea.
General disorders and administration site conditions	Asthenia, fever, malaise, reaction at the injection site.

Abrupt discontinuation of flupentixol may be accompanied by withdrawal symptoms. The most frequent symptoms are: nausea, vomiting, anorexia, diarrhoea, rhinorrhoea, sweating, myalgia, paraesthesia, insomnia, restlessness, anxiety and agitation. Patients may also experience dizziness, alternating sensations of heat and cold, and tremor.

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: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr/.

Symptoms:

Somnolence, coma, extrapyramidal symptoms, convulsions, shock, hyperthermia/hypothermia.

ECG changes, QT interval prolongation, torsades de pointes, cardiac arrest and ventricular arrhythmias have been reported in cases of overdose in association with medicinal products known for their cardiac effects.

Treatment:

Cardiorespiratory monitoring.

Do not use adrenaline as stimulation of beta-adrenergic receptors may lead to hypotension.

Pharmacotherapeutic class: antipsychotic - thioxanthene derivative, ATC code: N05AF01.

Incisive long-acting neuroleptic of the thioxanthene series.

Flupentixol is a potent inhibitor of the stimulation of adenylcyclase activity by dopamine in the corpus striatum.

Clinically, the activity of flupentixol is characterised by:

• an antipsychotic and anti-hallucinatory effect,
• an action on inhibition,
• a sedative effect at high doses,
• anticholinergic properties.

Flupentixol decanoate undergoes hydrolysis in the body, which releases flupentixol base.

In humans, the maximum serum concentration is reached between the 11th and the 17th day after injection.

The essential difference between FLUANXOL 4 PER CENT, oral solution, drops and FLUANXOL LP 100 mg/1 ml, injectable solution (IM) lies in their kinetics of action, which allows an daily oral administration to be replaced by injections spaced several weeks apart (on average 2 weeks apart).

Elimination is essentially hepatic.

Flupentixol is degraded by sulfoxidation and dealkylation.

The significant biliary excretion reflects an intense enterohepatic circulation.

Faecal excretion is seven times greater than urinary elimination.

In fertility studies in rats, flupentixol affected the pregnancy rate of females. Reproduction studies in mice, rats and rabbits did not demonstrate teratogenic effects.

In rats and rabbits, increases in post-implantation losses, resorption rate, or occasional abortions were observed at maternotoxic doses (2,5 to 4 times higher than the maximum therapeutic dose of 200 mg based on body surface area).

In rats, one study demonstrated an embryolethal effect at non-maternotoxic doses and below the maximum therapeutic dose of 200 mg (based on body surface area).

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

4 years.

After opening: the product must be used immediately.

Before opening: Store the ampoules in the outer packaging, protected from light.

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

List I

Marketing authorisation (AMM)

CIP 3400932634965 (1ampoule/1ml).

Price:

6,17 euros (1ampoule/1ml).

Remb Séc soc at 65%. Collect.