Clopixol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT CLOPIXOL® (CLOPIXOL®)

Composition:

Active substance: zuclopenthixol;

One tablet contains zuclopenthixol dihydrochloride equivalent to 2 or 10 mg of zuclopenthixol;

Excipients: potato starch; lactose monohydrate; microcrystalline cellulose; copovidone; glycerol (85%); talc; hydrogenated castor oil; magnesium stearate; hypromellose; macrogol 6000; titanium dioxide (E 171); iron oxide red (E 172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, round, film-coated tablets, pale red (2 mg) and light reddish-brown (10 mg) in color.

Pharmacotherapeutic group. Psycholeptics. Antipsychotic agents. Thioxanthene derivatives. Zuclopenthixol.

ATC code: N05AF05.

Pharmacological Properties

Pharmacodynamics

Zuclopenthixol is a neuroleptic agent belonging to the thioxanthene group.

The antipsychotic effect of neuroleptics is associated with blockade of dopamine receptors, and possibly also involves blockade of 5-HT receptors. In vitro, zuclopenthixol has high affinity for both dopamine D1 and D2 receptors, α1-adrenergic receptors, and 5-HT2 receptors, but no affinity for cholinergic muscarinic receptors. It has weak affinity for histaminergic (H1) receptors and does not exert blocking activity at α2-adrenergic receptors.

In vivo, affinity for D2 binding sites predominates over affinity for D1 receptors. Zuclopenthixol is a high-potency neuroleptic, as demonstrated in all behavioral studies of neuroleptic activity (ability to block dopamine receptors). At average daily oral dosing for antipsychotic treatment, affinity for blocking sites binding the dopamine D2 receptor has been observed in both in vitro and in vivo models.

Suppression of locomotor activity and prolonged sleep time induced by alcohol and barbiturates indicate the sedative effect of zuclopenthixol.

Like most other neuroleptics, zuclopenthixol increases serum prolactin levels.

Clinical Efficacy and Safety

Zuclopenthixol should be prescribed for the treatment of acute and chronic psychoses, as well as for the management of patients with intellectual disabilities accompanied by hyperactive and destructive behavior.

In addition to marked reduction or complete elimination of core symptoms of schizophrenia such as hallucinations, mania, and disordered thinking, zuclopenthixol effectively reduces associated symptoms such as hostility, suspicion, anxiety, and aggression.

Zuclopenthixol causes a transient, dose-dependent sedative effect. However, this primary sedation is usually beneficial during the initial phase of treatment. Tolerance to the non-specific sedative effect develops rapidly.

Pharmacokinetics

Absorption

Maximum plasma concentration is reached within 4 hours. Zuclopenthixol should be administered independently of food intake. Oral bioavailability is approximately 44%.

Distribution

The apparent volume of distribution (Vd)β is approximately 20 L/kg.

Plasma protein binding is about 98–99%.

Metabolism

Zuclopenthixol is metabolized via three main pathways: sulfoxidation, N-dealkylation of the side chain, and conjugation with glucuronic acid. Metabolites are devoid of psychopharmacological activity. Zuclopenthixol predominates over metabolites in the brain and other tissues.

Biological Transformation

The elimination half-life (T1/2β) is approximately 20 hours, and systemic clearance (Cls) is about 0.86 L/min. Zuclopenthixol is primarily eliminated via feces, with partial excretion (approximately 10%) in urine. Only about 0.1% of the dose is excreted unchanged in urine, indicating minimal renal drug load.

Zuclopenthixol passes into breast milk in small amounts. In women receiving the drug orally or as the decanoate ester, the steady-state ratio of breast milk concentration to serum concentration prior to the next dose administration was approximately 0.29.

Linearity

Kinetics are linear. Steady-state concentrations are achieved within 3–5 days. With administration of 20 mg zuclopenthixol orally once daily, the mean minimum steady-state level was approximately 25 nmol/L.

Elderly Patients

Pharmacokinetic parameters are significantly age-dependent.

Impaired Renal Function

Given the above-mentioned characteristics of drug elimination, it can be assumed that impaired renal function is unlikely to have a major impact on serum drug levels.

Impaired Hepatic Function

No data available.

Polymorphism

In vivo studies have shown that some metabolic pathways are subject to genetic polymorphism of sparteine/debrisoquine oxidation (CYP2D6).

Pharmacokinetic/Pharmacodynamic Interactions

A minimum (i.e., trough) serum concentration of 2.8–12 ng/mL (7–30 nmol/L) is recommended for maintenance therapy in patients with mild to moderate schizophrenia.

Clinical characteristics.

Indications.

Acute and chronic schizophrenia and other psychoses, especially those with symptoms such as hallucinations, mania, and thought disorders associated with excitement, restlessness, hostility, and aggression.

Manic phase of manic-depressive psychosis.

Excitement or other behavioral disorders in patients with intellectual disability.

Contraindications.

Hypersensitivity to any component of the drug, circulatory collapse, suppression of consciousness of any origin (e.g., due to alcohol, barbiturate, or opioid intoxication), coma.

Interaction with other medicinal products and other forms of interaction.

Combinations requiring caution during use

Zuclopenthixol may potentiate the effects of general anesthetics and anticoagulants and prolong the duration of action of neuromuscular blocking agents.

Anticholinergic effects of atropine or other medicinal products with anticholinergic properties may be enhanced.

Zuclopenthixol may enhance the sedative effects of alcohol, barbiturates, and central nervous system (CNS) inhibitors.

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

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

Antipsychotics may enhance the cardiodepressant effects of quinidine and affect the absorption of corticosteroids and digoxin.

The hypotensive effect of vasodilator antihypertensive agents such as hydralazine, α-blockers (e.g., doxazosin), or methyldopa may be enhanced.

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

Zuclopenthixol may reduce the efficacy of levodopa, adrenergic agents, and anticonvulsants; combinations with metoclopramide, piperazine, and anti-Parkinson drugs increase the risk of extrapyramidal disorders such as tardive dyskinesia.

Since zuclopenthixol is partially metabolized by CYP2D6, concomitant use of drugs capable of inhibiting this enzyme may impair zuclopenthixol elimination.

Prolongation of the QT interval associated with antipsychotic use may be intensified when used concomitantly with other agents capable of significantly prolonging the QT interval. Combinations with the following agents should be avoided:

• Class Ia and III antiarrhythmic agents (e.g., quinidine, amiodarone, sotalol, dofetilide).
• Certain antipsychotics (e.g., thioridazine).
• Certain macrolide antibiotics (e.g., erythromycin).
• Certain antihistamines (e.g., terfenadine, astemizole).
• Certain quinolone antibiotics (e.g., gatifloxacin, moxifloxacin).

The list above is not exhaustive; combinations with other individual agents capable of significantly prolonging the QT interval (such as cisapride, lithium) should also be avoided.

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

Antipsychotics may exhibit antagonism to the effects of adrenaline and other sympathomimetics and may neutralize the antihypertensive effects of guanethidine and similar adrenergic-blocking agents.

Special precautions for use.

Caution is required in patients with the following conditions: liver disease; heart disease or arrhythmias; severe respiratory disorders; renal impairment; epilepsy (and conditions predisposing to epilepsy such as alcohol withdrawal or brain injury); Parkinson's disease; narrow-angle glaucoma; benign prostatic hyperplasia; hypothyroidism; hyperthyroidism; myasthenia gravis; pheochromocytoma; and in patients who exhibit hypersensitivity to thioxanthenes or other antipsychotics.

Acute withdrawal symptoms, including nausea, vomiting, sweating, and insomnia, have been reported following abrupt discontinuation of antipsychotic agents. In addition, relapse of psychotic symptoms may occur, and cases of involuntary movement disorders (such as akathisia, dystonia, and dyskinesia) have been reported. Therefore, gradual withdrawal of the drug is recommended.

There is a potential risk of developing neuroleptic malignant syndrome (hyperthermia, muscle rigidity, altered consciousness, autonomic dysfunction) with the use of any neuroleptic agent. The risk may be higher when multiple agents are used. Fatal cases have primarily occurred in patients with pre-existing organic brain syndrome, mental retardation, or opioid and alcohol abuse.

Treatment: discontinue neuroleptics, provide symptomatic and general supportive care. Dantrolene and bromocriptine may be used.

Symptoms may persist for a week or longer after discontinuation of oral formulations and somewhat longer after administration of depot formulations.

Like other neuroleptics, zuclopenthixol should be used with caution in patients with organic brain syndrome, seizures, or progressive liver disease.

Rare cases of pathological changes in blood parameters have been reported. If signs of persistent infection occur in a patient, complete blood counts should be performed.

Like other antipsychotic agents, zuclopenthixol may alter insulin requirements and glucose tolerance, necessitating adjustment of antidiabetic therapy in patients with diabetes mellitus.

During maintenance therapy, especially when high doses are used, patients should be closely monitored, and periodic evaluation of the possibility of reducing the maintenance dose is recommended.

Like other agents within the therapeutic class of antipsychotics, zuclopenthixol may lead to QT interval prolongation. Pre-existing QT prolongation may increase the risk of serious arrhythmias. Therefore, zuclopenthixol should be used with caution in patients suspected of hypokalemia, hypomagnesemia, or with genetic predisposition to these conditions, as well as in patients with a history of cardiovascular disorders such as prolonged QT interval, marked bradycardia (<50 bpm), recent myocardial infarction, decompensated heart failure, or cardiac arrhythmia. Concomitant treatment with other antipsychotics should be avoided.

Venous thromboembolism (VTE) has been reported during antipsychotic therapy. Since patients treated with antipsychotics often have acquired VTE risk factors, all probable VTE risk factors should be identified before and during treatment with zuclopenthixol, and preventive measures should be taken.

Elderly patients

Elderly patients require careful monitoring, as they are particularly susceptible to adverse effects such as sedation, arterial hypotension, confusion, and disturbances in body temperature regulation.

Cerebrovascular disorders

In randomized, placebo-controlled studies of some atypical antipsychotics in patients with dementia, approximately a threefold increased risk of cerebrovascular events has been observed. The mechanism of this increased risk is unknown. An increased risk cannot be excluded with the use of other antipsychotics or in other patient populations. Zuclopenthixol should be used with caution in patients with risk factors for stroke.

Increased mortality in elderly patients with dementia

Data from two large clinical trials indicate that elderly patients with dementia treated with antipsychotics have a slightly higher risk of mortality compared to patients not receiving these agents. Data are insufficient to precisely define this risk, and the cause of the increased risk is unknown.

Zuclopenthixol is not indicated for the treatment of behavioral disorders associated with dementia.

Excipients

Tablets contain lactose monohydrate. This medicine should not be administered to patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Tablets contain hydrogenated castor oil, which may cause gastrointestinal disturbances or diarrhea.

Use during pregnancy or breastfeeding.

Zuclopenthixol should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the fetus.

Neonates whose mothers have used antipsychotics (including zuclopenthixol) during the third trimester of pregnancy may be at risk of developing adverse effects, including extrapyramidal symptoms or withdrawal symptoms, which may vary in severity and duration after delivery. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding difficulties have been reported. Therefore, neonates require close monitoring.

Animal studies have shown reproductive toxicity.

Zuclopenthixol is excreted in breast milk in low concentrations, and its effect on the infant at therapeutic doses is unlikely. The dose received by the infant through breast milk is less than 1% of the mother's daily dose and depends on the mother's body weight (mg/kg). Breastfeeding may continue during treatment with zuclopenthixol if clinically justified, but medical supervision of the infant is recommended, especially during the first 4 weeks after birth.

Fertility

Adverse effects such as hyperprolactinemia, galactorrhea, amenorrhea, erectile dysfunction, and absence of ejaculation have been reported. These effects may negatively affect male or female sexual function and fertility.

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

Administration of zuclopenthixol to male and female rats was associated with some delay in mating. In an experiment where zuclopenthixol was administered with food, impaired mating performance and reduced fertility were observed.

Ability to influence reaction speed while driving or operating machinery.

Clopixol is a sedative agent. Patients receiving psychotropic medicinal products or after alcohol consumption may experience reduced attention and concentration. They should be warned about the possible effects of the drug on their ability to drive or operate machinery.

Patients should not drive if they experience blurred vision.

Method of Administration and Dosage

Adults

Dosage should be individually adjusted according to the patient's condition. Generally, treatment should be initiated with low doses, which should then be increased as rapidly as possible to the optimal effective level, depending on the clinical response. The maintenance dose is usually taken once daily in the evening. Tablets should be swallowed with water.

Acute schizophrenia and other acute psychoses. Severe acute states of excitement. Mania

The usual dosage is 10–50 mg per day. In cases of severe disorders and moderately severe conditions, an initial dose of 20 mg per day may be increased, if necessary, by 10–20 mg every 2–3 days up to 80 mg per day or more. The maximum single dose is 40 mg and the maximum daily dose is 150 mg.

Chronic schizophrenia and other chronic psychoses

The maintenance dose is 20–40 mg per day.

Agitation in patients with intellectual disability

The usual dosage is 10–20 mg per day; if necessary, the dose may be increased to 30–40 mg per day.

Elderly patients. Lower therapeutic doses should be prescribed.

Renal impairment. Zuclopenthixol may be administered in usual doses to patients with impaired renal function.

Hepatic impairment. Dose titration should be cautious, and, if possible, monitoring of plasma drug levels is recommended.

Children.

Use in children and adolescents is not recommended due to lack of clinical data.

Overdose.

Symptoms: drowsiness, coma, extrapyramidal disorders, seizures, arterial hypotension, shock, hypothermia or hyperthermia.

When overdose occurs concomitantly with agents capable of affecting cardiac function, cases of ECG changes, QT prolongation, torsades de pointes, ventricular arrhythmias, and cardiac arrest have been reported.

Treatment: symptomatic and supportive. Measures to maintain respiratory and cardiovascular function should be implemented.

Epinephrine (adrenaline) should not be used, as it may lead to further reduction in blood pressure. Seizures may be treated with diazepam, and movement disorders with biperiden.

If necessary, the following specific measures may be taken:

• Administration of anticholinergic anti-Parkinson drugs in case of extrapyramidal symptoms.
• Sedation (with benzodiazepines) in the unlikely event of nervous excitement, emotional agitation, or seizures.
• Intravenous infusion of noradrenaline in saline solution in case of shock. Adrenaline (epinephrine) must not be administered.
• Gastric lavage should be considered as appropriate.

Adverse Reactions

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

Extrapyramidal disorders may develop, particularly in the initial phase of treatment. In most cases, these can be managed by dose reduction and/or administration of anti-parkinsonian agents. Routine prophylactic use of the latter is not recommended. Anti-parkinsonian agents do not alleviate tardive dyskinesia and may even exacerbate it. Dose reduction or, if possible, discontinuation of zuclopenthixol therapy is recommended. In cases of persistent akathisia, treatment with a benzodiazepine or propranolol is recommended.

The frequency of the adverse reactions listed in the table below is defined as:

very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), or not known (cannot be estimated from available data).

There have been reports of rare cases of QT prolongation, ventricular arrhythmias: ventricular fibrillation, ventricular tachycardia, torsades de pointes, cardiac arrest, and sudden fatal outcome associated with the use of medicinal products belonging to the therapeutic class of antipsychotics, including zuclopenthixol.

Sudden discontinuation of zuclopenthixol may be accompanied by 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, fluctuating sensations of warmth or cold, and tremor. Symptoms usually occur within 1–4 days after discontinuation and subside within 7–14 days.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children. The medicinal product does not require special storage conditions.

Packaging. 100 tablets in a plastic container in a cardboard box.

Prescription status. Prescription only.

Manufacturer. H. Lundbeck A/S.

Manufacturer's address.

Ottiliavej 9, 2500 Valby, Denmark.