Pharmacotherapeutic group: Neuroleptics (antipsychotics). ATC-code: N05AF01.
Pharmacology: Fluanxol Depot: Fluanxol Depot contains the active substance flupentixol decanoate. Fluanxol Depot belongs to a group of medicines known as antipsychotics (also called neuroleptics).
These medicines act on nerve pathways in specific areas of the brain and help to correct certain chemical imbalances in the brain that are causing the symptoms of the illness.
Pharmacodynamics: Mechanism of action: Fluanxol: Flupentixol is a neuroleptic of the thioxanthene group.
Flupentixol is a mixture of two geometric isomers, the active flupentixol (cis(Z)-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 safety: 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.
Pharmacokinetics: 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 N-dealkylation 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 previously mentioned 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.
Toxicology: Preclinical safety data: 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.
Reproduction 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.