Fluanxol film-coated tablets 1 mg container No. 100

Instructions Fluanxol film-coated tablets 1 mg container No. 100

Composition

active ingredient: flupentixol;

1 tablet contains flupentixol dihydrochloride equivalent to 0.5 mg or 1 mg flupentixol;

excipients: betadex; lactose, monohydrate; corn starch; hydroxypropylcellulose; microcrystalline cellulose; croscarmellose sodium; talc; hydrogenated vegetable oil; magnesium stearate;

shell: partially hydrolyzed polyvinyl alcohol, titanium dioxide (E 171), macrogol 3350, talc, iron oxide yellow (E 172), macrogol 6000.

Dosage form

Film-coated tablets.

Main physicochemical properties:

0.5 mg: round, slightly biconvex, yellow, film-coated tablets marked FD; 1 mg: oval, slightly biconvex, yellow, film-coated tablets marked FF.

Pharmacotherapeutic group

Psycholeptics. Antipsychotics. Thioxanthene derivatives. Flupentixol.

ATX code N05A F01.

Pharmacological properties

Pharmacodynamics.

Flupentixol is a neuroleptic from the thioxanthene group.

Flupentixol is a mixture of two geometric isomers, active flupentixol and trans(E)-flupentixol, in an approximate 1:1 ratio.

The antipsychotic effect of neuroleptics is associated with the blockade of dopamine receptors, as well as the possible involvement of 5HT receptor blockade. In vitro and in vivo, flupentixol has a high affinity for both dopamine D1 and D2 receptors, in contrast to fluphenazine, which is selective for D2 in vivo. The atypical antipsychotic clozapine has a similar affinity for D1 and D2 receptors to flupentixol in vitro and in vivo.

Flupentixol has a high affinity for α1-adrenoceptors and 5HT2 receptors, although somewhat lower than chlorprothixene, high-dose phenothiazines, and clozapine, but has no affinity for cholinergic muscarinic receptors. It exhibits weak antihistaminergic properties and has no α2-adrenoceptor blocking activity.

Flupentixol is a potent neuroleptic, as demonstrated by all behavioral studies of neuroleptic activity (dopamine receptor blocking ability). At average daily dosages and oral use for antipsychotic treatment, affinity for the dopamine D2 receptor binding sites is observed in in vitro and in vivo models.

Perioral movements in rats depend on D1 receptor stimulation or D2 receptor population blockade. Movements can be prevented by flupentixol. Similarly, results from studies in monkeys indicate that oral hyperkinesia is largely due to D1 receptor stimulation and less to D2 receptor hypersensitivity. This suggests that D1 activation is responsible for the development of a similar effect in humans, i.e., the development of dyskinesia. Thus, D1 receptor blockade should be beneficial in preventing the development of dyskinesia in humans.

Flupentixol prolongs alcohol- and barbiturate-induced sleep in mice only at very high doses, suggesting a very weak sedative effect in clinical use.

Like most other neuroleptics, flupentixol dose-dependently increases serum prolactin levels.

Fluanxol has a broad spectrum of activity that is dose-dependent.

Flupentixol in low doses (1–2 mg/day) causes antidepressant, anxiolytic, and activating effects.

In medium doses (3–25 mg/day), flupentixol is prescribed for the treatment of acute and chronic psychoses, and in this dosage range, the drug practically does not exhibit a nonspecific sedative effect and is unsuitable for the treatment of patients with severe psychomotor agitation. In addition to a significant reduction or complete elimination of the core symptoms of schizophrenia, such as hallucinations, delusions, and thought disorders, flupentixol also has disinhibitory (anti-autistic and activating) properties, improves mood, which is especially necessary in the treatment of apathetic, solitary, depressed patients with poor motivation.

The antipsychotic effect increases with increasing dose; in addition, some sedation should be expected. Flupentixol produces anxiolytic effects across the entire dose range, and even at high doses, the disinhibitory and mood-elevating effects are maintained. Treatment with high doses does not increase the incidence of extrapyramidal symptoms.

Pharmacokinetics.

Below is data on the active isomer.

Absorption.

The bioavailability of flupentixol after oral administration is approximately 40%, and the maximum concentration in serum is reached in 4–5 hours.

Distribution.

The apparent volume of distribution (Vd)β is approximately 14.1 l/kg. Plasma protein binding is approximately 99%.

Biotransformation.

The metabolism of flupentixol occurs via three main pathways: sulfoxidation, N-dealkylation of the side chain, and glucuronic acid conjugation. The metabolites have no psychopharmacological activity. Flupentixol predominates over the metabolites in the brain and other tissues.

Breeding

When tritium-labeled flupentixol was administered to humans, the elimination profile showed that its excretion in feces was approximately 4 times greater than its excretion in urine.

Flupentixol passes into breast milk in small amounts. In women, the milk-to-serum concentration ratio is on average 1.3.

Linearity.

The kinetics are linear, with steady-state plasma concentrations achieved within 7 days. With 5 mg flupentixol administered orally once daily, the mean trough steady-state level was approximately 1.7 ng/mL (3.9 nmol/L).

Elderly patients.

Pharmacokinetic studies in elderly patients have not been conducted. However, the pharmacokinetic parameters of a related thioxanthene drug, zuclopenthixol, do not appear to be significantly dependent on patient age.

Based on the above characteristics, it can be assumed that decreased renal function may not have a significant effect on serum drug levels.

There are no data on the effect of liver dysfunction on the pharmacokinetic parameters of the drug.

Pharmacokinetic/Pharmacodynamic Interaction

A trough (i.e., concentration measured before the next dose) serum (plasma) concentration of 1-3 ng/mL (2-8 nmol/L) is suggested as recommended for maintenance treatment of patients with schizophrenia with mild to moderate severity of illness.

Indication

Depression accompanied by anxiety, asthenia, and loss of initiative.

Chronic neurotic disorders accompanied by anxiety, depression, and inactivity.

Psychosomatic disorders with asthenic reactions.

Schizophrenia and other psychoses, especially with symptoms such as hallucinations, delusions, and thought disorders, are complicated by apathy, anergy, depressed mood, and solitude.

Contraindication

Hypersensitivity to any component of the drug.

Severe depression requiring electroconvulsive therapy or hospitalization; states of emotional agitation or hyperactivity, including mania.

Circulatory collapse, central nervous system depression of any origin (e.g. due to alcohol, barbiturate or opioid intoxication), coma.

Not recommended for use in easily excitable patients and in patients in a state of nervous excitement.

Interaction with other medicinal products and other types of interactions

Combinations requiring precautions for use

Flupentixol may enhance the sedative effects of alcohol, barbiturates and central nervous system inhibitors. Flupentixol may potentiate the effects of general anesthetics and anticoagulants and prolong the duration of action of neuromuscular blocking agents.

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

Neuroleptics may enhance or reduce the effect of antihypertensive agents; the hypotensive effect of guanethidine and similarly acting agents is attenuated.

Concomitant use of neuroleptics and lithium or sibutramine increases the risk of neurotoxicity.

Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism and may worsen diabetes control.

Antipsychotics may antagonize the effects of adrenaline and other sympathomimetics and neutralize the antihypertensive effects of guanethidine, possibly clonidine, and similar adrenoblocking agents. Antipsychotics may reduce the effects of levodopa, adrenergic drugs, and anticonvulsants.

The anticholinergic effects of atropine or other drugs with anticholinergic properties may be enhanced.

Concomitant use of drugs such as metoclopramide, piperazine or antiparkinsonian drugs may increase the risk of extrapyramidal disorders such as tardive dyskinesia.

Flupentixol may reduce the effects of levodopa and adrenergic agents, and the combination with metoclopramide and piperazine increases the risk of developing extrapyramidal symptoms.

The QT prolongation associated with antipsychotic drugs may be potentiated by concomitant use with other drugs that can significantly prolong the QT interval. Combinations of such drugs should be avoided. Relevant classes include:

class Ia and III antiarrhythmic drugs (e.g. quinidine, amiodarone, sotalol, dofetilide);

some antipsychotics (e.g. thioridazine);

some macrolide antibiotics (e.g. erythromycin);

some antihistamines (e.g. terfenadine, astemizole);

some quinolone antibiotics (e.g. gatifloxacin, moxifloxacin).

The above list is not exhaustive; combination with other individual drugs that can significantly prolong the QT interval (such as cisapride, lithium) should be avoided.

Agents that alter electrolyte balance, such as thiazide diuretics (hypokalemia), and agents that increase flupentixol concentrations should also be used with caution as they may increase the risk of QT prolongation and malignant arrhythmias.

Application features

Caution should be exercised in patients with the following conditions: liver disease; heart disease or arrhythmias; severe respiratory disease; renal failure; epilepsy (and conditions predisposing to epilepsy, such as alcohol withdrawal or brain damage); Parkinson's disease; narrow-angle glaucoma; prostatic hypertrophy; hypothyroidism; hyperthyroidism; myasthenia gravis; pheochromocytoma and patients with hypersensitivity to thioxanthenes or other antipsychotics.

Relapse of depressive symptoms after abrupt drug withdrawal is rare.

Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia, have been reported following abrupt discontinuation of thioxanthenes and similar drugs. Movement disorders (including akathisia, dystonia and dyskinesia) have been reported. Therefore, gradual withdrawal is recommended.

No cases of drug addiction have been reported to date.

The possibility of developing neuroleptic malignant syndrome (hyperthermia, muscle rigidity, impaired consciousness, autonomic dysfunction) exists with the use of any neuroleptic. The risk is potentially higher with the use of several agents. Fatal cases have been observed mainly in the presence of pre-existing organic brain syndrome, mental retardation, opiate and alcohol abuse.

Treatment: discontinuation of the neuroleptic, symptomatic and general supportive measures. Dantrolene and bromocriptine may be used.

Symptoms may persist for a week or more after stopping oral forms and somewhat longer after taking depot forms of the drugs.

Rare cases of abnormal blood counts, including thrombocytopenia, have been reported. Complete blood counts should be performed if the patient shows signs of persistent infection.

As with other neuroleptics, flupentixol should be used with caution in the treatment of patients with organic brain syndrome, seizures, and progressive liver disease.

Flupentixol in doses up to 25 mg/day is not recommended for the treatment of excitable, hyperactive patients, as its activating effect may enhance such characteristics. Tranquilizers or sedative neuroleptics should be discontinued gradually when switching to flupentixol treatment.

Like other antipsychotics, flupentixol may alter insulin and glucose profiles in the body, requiring adjustment of antidiabetic therapy in patients with diabetes.

During maintenance therapy, especially when using high doses, patients should be carefully monitored and the possibility of reducing the maintenance dose should be periodically assessed.

As with other drugs in the antipsychotic class, flupentixol may cause QT prolongation. Existing QT prolongation may increase the risk of malignant arrhythmias. Therefore, flupentixol should be used with caution in patients with suspected hypokalemia, hypomagnesemia or a genetic predisposition to such conditions, as well as in patients with a history of cardiovascular disease, such as prolonged QT interval, significant bradycardia (<50 beats/min), recent myocardial infarction, uncompensated heart failure or cardiac arrhythmias. Concomitant treatment with other antipsychotics should be avoided.

Suicide/suicidal thoughts or clinical worsening

Depression is associated with an increased risk of suicidal ideation, self-harm and suicide. This risk persists until significant remission occurs. As improvement may not occur within the first few weeks of treatment or longer, patients should be closely monitored until improvement occurs. General clinical experience suggests that the risk of suicide may be increased in the early stages of recovery. Other psychiatric disorders for which flupentixol is prescribed may also be associated with an increased risk of suicide and related events. In addition, these conditions may be comorbid with depressive disorder. The same precautions should be observed when treating patients with major depressive disorder and other psychiatric disorders. Patients with a history of suicide-related events or patients who demonstrate a significant degree of suicidal ideation prior to initiation 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 antidepressants in patients with psychiatric disorders showed an increased risk of suicidal behavior in patients under 25 years of age who were treated with antidepressants compared with those who took placebo.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients taking antipsychotic drugs often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with flupentixol and preventive measures should be taken.

Elderly patients.

Elderly patients require close monitoring as they are particularly susceptible to adverse effects such as sedation, hypotension, confusion and changes in body temperature.

Cerebrovascular diseases

An approximately three-fold increased risk of cerebrovascular adverse events has been observed with some atypical antipsychotics in randomized placebo-controlled trials in patients with dementia. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics and for other patient populations. Flupentixol should be used with caution in patients with risk factors for stroke.

Increased risk of death in elderly patients with dementia

Research has shown that elderly patients with dementia who are treated with antipsychotic medications have a slightly increased risk of death compared with those who are not treated with such medications. There are insufficient data to accurately estimate the magnitude of the risk, and the reason for the increased risk is unknown.

Flupentixol is not indicated for the treatment of behavioral disturbances associated with dementia.

Excipients

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

Use during pregnancy or breastfeeding

Pregnancy

Since the safety of Fluanxol during human pregnancy has not been established, flupentixol should not be administered during pregnancy, especially in the first and last trimesters, unless the expected benefit to the patient outweighs the theoretical risk to the fetus.

Neonates whose mothers have taken antipsychotics (including flupentixol) during the third trimester of pregnancy may be at risk of adverse reactions, including extrapyramidal disorders and/or withdrawal symptoms, the severity and duration of which may vary after delivery. Cases of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress or feeding disorders have been reported. Therefore, close monitoring of the condition of the neonate is necessary.

Animal studies have shown reproductive toxicity.

Lactation

If the use of Fluanxol is considered absolutely necessary, nursing mothers should be advised to discontinue breastfeeding.

Fertility

Side effects such as hyperprolactinemia, galactorrhea, amenorrhea, decreased libido, erectile dysfunction, and ejaculation failure have been reported. These events may negatively affect female or male sexual function and fertility.

If clinically significant hyperprolactinemia, galactorrhea, amenorrhea, or sexual dysfunction occurs, dose reduction (if possible) or discontinuation should be considered. Effects are reversible upon discontinuation of the drug.

In preclinical studies of the effect of the drug on fertility in rats, flupentixol had a negligible effect on the pregnancy rate in female rats.

Ability to influence reaction speed when driving vehicles or other mechanisms

Fluanxol is a non-sedating agent in the low to medium dose range. However, patients who are prescribed psychotropic medications or after consuming alcohol may experience some reduction in general alertness and concentration and should be warned about the possible impact of their treatment on their ability to drive and use machines.

Patients should not drive if they experience blurred vision.

Method of administration and doses

Adults

Depression. Chronic neurotic disorders. Psychosomatic disorders

Initially 1 mg/day as a single dose in the morning or 0.5 mg twice daily. After a week, the dose may be increased to 2 mg/day if the clinical response is insufficient. Daily doses greater than 2 mg should be divided into separate doses up to a maximum of 3 mg.

Elderly patients

Elderly patients should be given half the recommended dose.

Patients usually begin to respond to flupentixol within two or three days of use. If the maximum dose is not effective for a week, the drug should be discontinued.

Schizophrenia and other psychoses

Adults

The dosage of the drug is determined individually, according to the patient's condition. In general, it is necessary to start with low doses and increase them to the optimally effective level as soon as possible, according to the therapeutic effect. The maintenance dose can usually be taken once in the morning.

Initially, 3–15 mg/day in 2 or 3 divided doses, increasing to 40 mg/day if necessary. The maintenance dose is usually 5–20 mg/day, which can be taken once daily in the morning.

Elderly patients: Lower doses should be prescribed.

Hepatic impairment: Careful selection of the therapeutic dose and, if possible, determination of serum drug levels are recommended.

Method of administration

Swallow the tablets with water.

Children

The use of the drug is not recommended due to insufficient clinical data.

Overdose

Symptoms: drowsiness, coma, extrapyramidal disorders, convulsions, hypotension, shock, hypo- or hyperthermia.

The highest oral single dose administered in clinical trials was 80 mg and up to 320 mg/day.

In case of simultaneous overdose with drugs that can affect cardiac activity, cases of ECG changes, QT prolongation, torsades de pointes, cardiac arrest and ventricular arrhythmias have been observed.

Treatment: symptomatic and supportive. Gastric lavage and sorbents should be performed as soon as possible. Measures should be taken to maintain the respiratory and cardiovascular systems.

The following special measures may be taken if necessary:

Use of anticholinergic antiparkinsonian drugs in case of extrapyramidal symptoms.

Sedation (benzodiazepines) in the unlikely event of nervous excitement or emotional agitation or seizures.

Administer norepinephrine intravenously by infusion in saline if the patient is in shock.

It is necessary to weigh the feasibility of gastric lavage.

Epinephrine (adrenaline) should not be used as this may further lower blood pressure. Convulsions can be treated with diazepam and extrapyramidal symptoms with biperiden.

Side effects

Cases of suicidal thoughts and suicidal behaviour have been reported during flupentixol therapy or early after drug withdrawal (see section 4.4).

Undesirable effects are in most cases dose-dependent. Their frequency and severity are more pronounced at the beginning of therapy and decrease with further treatment.

Extrapyramidal symptoms may develop, especially in the initial phase of therapy. In most cases, they are corrected by reducing the dosage and/or antiparkinsonian drugs. Regular prophylactic use of the latter is not recommended. Antiparkinsonian drugs do not eliminate tardive dyskinesia and may exacerbate it. It is recommended to reduce the dose or, if possible, discontinue treatment with flupentixol. In case of persistent akathisia, it is recommended to use a benzodiazepine or propranolol.

Adverse reactions are defined by frequency in the table below 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 unknown (cannot be estimated from the available data).

* Cases of suicidal ideation and suicidal behavior have been reported during flupentixol therapy or early after discontinuation of treatment.

There have been rare reports of QT prolongation, ventricular arrhythmias – ventricular fibrillation, ventricular tachycardia, torsades de pointes – and sudden death with the use of medicinal products belonging to the therapeutic class of antipsychotics, including flupentixol.

Abrupt discontinuation of flupentixol may cause withdrawal symptoms, the most common of which are nausea, vomiting, anorexia, diarrhea, rhinorrhea, sweating, myalgia, paresthesia, insomnia, restlessness, anxiety, and agitation. Patients may also experience dizziness, alternating sensations of heat or cold, and tremor. Symptoms usually begin within 1 to 4 days of discontinuation and subside within 7 to 14 days.

Expiration date

3 years.

Storage conditions

No special storage conditions required. Keep out of the reach of children.

Packaging

100 tablets in a plastic container in a cardboard box.

Vacation category

According to the recipe.

Producer

H. Lundbeck A/S (H. Lundbeck A/S).

Address

Ottiliavej 9, 2500 Valby, Denmark.