Clopixol-acuphase

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT KLOPIKSOLO-AKUFAS (CLOPIXOL-ACUPHASE®)

Composition:

Active substance: zuclopenthixol;

1 ml of solution contains 50 mg of zuclopenthixol acetate;

Excipients: medium-chain triglycerides.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear, yellowish, oily solution, almost free from mechanical inclusions.

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

ATC code N05AF05.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of Action

Zuclopenthixol is a neuroleptic agent belonging to the thioxanthene group.

The antipsychotic effect of neuroleptics is associated with blockade of dopamine receptors, as well as possible involvement of 5-HT receptor (5-hydroxytryptamine) blockade. 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 effects on α2-adrenergic receptors.

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

Like most other neuroleptics, zuclopenthixol increases serum prolactin levels.

A pronounced effect occurs within 4 hours after parenteral administration of the oily solution of zuclopenthixol acetate. A somewhat more pronounced effect is observed between one and three days after injection. Over the following days, the effect rapidly diminishes.

Clinical Efficacy and Safety

Zuclopenthixol acetate is used for initial treatment of acute psychoses, mania, and exacerbations of chronic psychoses. A single injection of zuclopenthixol acetate provides marked and rapid alleviation of psychotic symptoms. The effect lasts from 2 to 3 days, and usually one or two injections are sufficient to achieve the desired effect, after which transition to oral or depot formulations is possible. 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, suspiciousness, anxiety, and aggressiveness.

Zuclopenthixol exhibits a transient, dose-dependent sedative effect. This initial sedation is generally beneficial in the early phase of psychosis, as it calms the patient until the antipsychotic effect becomes established. Non-specific sedation develops rapidly after injection, becomes evident within 2 hours, peaks at 8 hours, then significantly decreases and remains mild despite repeated injections.

Zuclopenthixol acetate is indicated for the treatment of psychotic patients with agitation, restlessness, hostility, or aggression.

Pharmacokinetics.

Absorption

Through esterification of zuclopenthixol with acetic acid, zuclopenthixol is converted into a more lipophilic substance—zuclopenthixol acetate.

After injection, zuclopenthixol acetate undergoes enzymatic hydrolysis into the active component zuclopenthixol and acetic acid.

The elimination half-life is approximately 32 hours (reflecting release from the depot). Maximum serum concentration of zuclopenthixol is reached 24–48 hours (on average, 36 hours) after injection.

Distribution

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

Plasma protein binding is approximately 98–99%.

Biological Transformation

Zuclopenthixol is metabolized via three main pathways: sulfoxidation, N-dealkylation of the side chain, and conjugation with glucuronic acid.

Metabolites are not neuroleptically active and are excreted primarily in feces and partially in urine (10%). The elimination half-life (t1/2β) of zuclopenthixol is approximately 20 hours, and systemic clearance (Cls) is approximately 0.86 L/min.

Zuclopenthixol is excreted predominantly in feces and to some extent in urine (approximately 10%). Only about 0.1% of the dose is excreted unchanged in urine, indicating minimal drug load on the kidneys.

Zuclopenthixol crosses the placental barrier in small amounts and is also excreted in small quantities into breast milk. The mean ratio of active substance concentration in breast milk to active substance concentration in maternal serum immediately before the next dose during steady-state therapy with oral or intramuscular zuclopenthixol in decanoate form was approximately 0.29.

Linearity

Kinetics are linear. The mean maximum serum level of zuclopenthixol after administration of 100 mg zuclopenthixol acetate is 102 nmol/L (41 ng/mL). Three days after injection, serum levels are approximately one-third of the maximum, i.e., 35 nmol/L (14 ng/mL).

Elderly Patients

Pharmacokinetic parameters are significantly influenced by patient age.

Impaired Renal Function

Given the above-mentioned excretion characteristics, 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 certain metabolic pathways are subject to genetic polymorphism of debrisoquine/sparteine oxidation (CYP2D6).

Clinical characteristics.

Indications.

Initial treatment of acute psychoses, manic states, and chronic psychoses in the phase of exacerbation.

Contraindications.

Hypersensitivity to any component of the medicinal product.

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 acetate may enhance the sedative effects of alcohol, barbiturates, and other central nervous system inhibitors.

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.

Neuroleptics may either enhance or diminish the effects of antihypertensive agents; the antihypertensive effect of guanethidine and similar drugs is reduced.

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

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

Zuclopenthixol acetate may reduce the effect of levodopa, adrenergic agents, and anticonvulsants.

Combination with metoclopramide, piperazine, or antiparkinsonian drugs increases the risk of developing extrapyramidal disorders such as tardive dyskinesia.

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

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

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

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

• Class Ia and III antiarrhythmic agents (e.g., quinidine, amiodarone, sotalol, dofetilide).
• Certain antipsychotic agents (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 drugs capable of significantly prolonging the QT interval (such as cisapride, lithium) should also be avoided.

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.

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

Special precautions for use.

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

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

Treatment: discontinue neuroleptic agents, provide symptomatic and general supportive measures. Dantrolene and bromocriptine may be used.

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

Like other neuroleptics, zuclopenthixol acetate should be used with caution in treating patients with organic brain disorders, seizures, or progressive liver, kidney, or cardiovascular 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 acetate may alter insulin requirements and glucose tolerance, necessitating adjustment of antidiabetic therapy in patients with diabetes mellitus.

Like other agents belonging to the therapeutic class of antipsychotics, zuclopenthixol acetate may lead to QT interval prolongation. Pre-existing QT prolongation may increase the risk of life-threatening arrhythmias. Therefore, zuclopenthixol acetate should be used with caution in patients suspected of hypokalemia, hypomagnesemia, or with genetic predisposition to such conditions, as well as in patients with a history of cardiovascular diseases, such as prolonged QT interval, significant bradycardia (<50 bpm), recent myocardial infarction, decompensated heart failure, or cardiac arrhythmias. Concomitant use with other antipsychotic drugs should be avoided.

Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic agents. Since patients receiving antipsychotics often have acquired VTE risk factors, all potential VTE risk factors should be identified before and during treatment with zuclopenthixol acetate, 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 trials, some atypical antipsychotics have been associated with approximately a threefold increased risk of cerebrovascular adverse events in elderly patients with dementia. The mechanism of this increased risk is unknown. An increased risk cannot be ruled out with the use of other antipsychotics or in other patient populations. Zuclopenthixol acetate should be used with caution in patients with risk factors for stroke.

Increased mortality in elderly patients with dementia

Clinical trial data indicate that elderly patients with dementia treated with antipsychotic agents have a slightly higher risk of mortality compared to those not receiving these agents. Data are insufficient to precisely quantify this risk, and the reason for the increased risk is unknown.

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

Use during pregnancy or breastfeeding.

Pregnancy

Zuclopenthixol acetate should not be administered during pregnancy. It should only be used under medical supervision if the expected benefit to the patient outweighs the theoretical risk to the fetus.

Neonates whose mothers have used antipsychotic agents (including zuclopenthixol acetate) during the third trimester of pregnancy may be at risk of developing adverse effects, including extrapyramidal disorders 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.

Lactation

Zuclopenthixol is excreted in breast milk in low concentrations, and its effect on infants 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 be continued during zuclopenthixol treatment if clinically important, but medical supervision of the infant is recommended, especially during the first 4 weeks after birth.

Fertility

Cases of hyperprolactinemia, galactorrhea, amenorrhea, erectile dysfunction, and absence of ejaculation have been reported (see section "Adverse reactions"). These conditions may negatively affect sexual function and/or fertility in women and/or men.

If possible, the dose should be reduced or the drug discontinued if clinically significant hyperprolactinemia, galactorrhea, amenorrhea, or sexual dysfunction develops. These disorders are reversible upon discontinuation of the drug.

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 affect reaction speed when driving vehicles or operating machinery.

Clopixol-Acuphase is a sedative agent. Patients receiving psychotropic medications or after alcohol consumption may experience reduced attention and concentration. They should be warned about the potential effect of the drug on their ability to drive vehicles or operate machinery.

Patients should not drive vehicles if they experience blurred vision.

Dosage and Administration

Adults

Dosage should be individually adjusted according to the patient's condition.

The usual recommended dose for adults is 50–150 mg (1–3 mL) administered as an intramuscular injection. The injection may be repeated if necessary, preferably at 2–3 day intervals. In some patients, an additional injection may be given 24–48 hours after the first injection.

Zuclopenthixol acetate is not intended for long-term use, and the duration of treatment should not exceed 2 weeks. The maximum cumulative dose during the entire course of therapy should not exceed 400 mg, and the number of injections should not exceed 4.

Maintenance therapy should be continued with oral zuclopenthixol or zuclopenthixol decanoate, according to the following schemes:

1. Switching to oral zuclopenthixol therapy

Two to three days after the last injection of zuclopenthixol acetate (100 mg), the patient should start receiving an oral daily dose of 40 mg, preferably divided into several doses. If necessary, the dose may be increased by 10–20 mg every 2–3 days up to 75 mg per day or more.

2. Switching to zuclopenthixol decanoate therapy

Concurrently with the last injection of zuclopenthixol acetate (100 mg), 200–400 mg (1–2 mL) of zuclopenthixol decanoate 200 mg/mL should be administered intramuscularly, and subsequent intramuscular injections should be repeated every 2 weeks. Higher doses or shorter intervals between injections may be used if required.

Zuclopenthixol acetate and zuclopenthixol decanoate may be mixed in the same syringe and administered as a single injection (co-injection). Subsequent doses of zuclopenthixol decanoate and the intervals between injections should be adjusted according to the patient's clinical condition.

Elderly patients. Dose reduction may be necessary. The maximum single dose should not exceed 100 mg.

Renal impairment. Klopixol-Acuphase can be administered at usual doses in patients with renal impairment.

Hepatic impairment. Patients with hepatic impairment should receive half the usual dose. If possible, serum drug levels should also be monitored.

Administration method

Klopixol-Acuphase is administered by deep intramuscular injection into the upper outer quadrant of the gluteal muscle. Injections exceeding 2 mL in volume should be divided and administered at two separate sites. Local tolerance is good.

Children

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

Overdose

Overdose is unlikely due to the pharmaceutical formulation.

Symptoms: Somnolence, coma, hypo- or hyperthermia, extrapyramidal symptoms, seizures, arterial hypotension, shock, hyperthermia/hypothermia. Changes in ECG including QT prolongation, cases of torsades de pointes, ventricular arrhythmias, and cardiac arrest have been reported when extremely high doses of the drug are administered concomitantly with agents affecting cardiac function.

Treatment: Symptomatic and supportive. Measures should be taken to maintain respiratory and cardiovascular function. Epinephrine should not be used, as it may lead to further lowering of blood pressure. Seizures may be treated with diazepam, and movement disorders with biperiden.

Adverse reactions.

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

Extrapyramidal disorders may develop, particularly during the first few days after injection and in the initial phase of therapy. In most cases, these can be managed by reducing the dosage and/or using anti-parkinsonian drugs. Routine prophylactic use of the latter is not recommended. Anti-parkinsonian drugs do not alleviate tardive dyskinesia and may even exacerbate it. Dose reduction or, if possible, discontinuation of zuclopenthixol treatment 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 follows: 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 and 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 acetate.

Sudden discontinuation of zuclopenthixol acetate may lead to withdrawal symptoms, the most common of which are nausea, vomiting, anorexia, diarrhea, rhinorrhea, sweating, myalgia, paraesthesia, insomnia, restlessness, anxiety, and agitation. Patients may also experience dizziness, sensations of heat or cold, and tremor. Symptoms usually occur within 1–4 days after discontinuation and subside within 7–14 days.

Shelf life. 3 years.

Storage conditions. No special temperature storage requirements. Store in the original packaging to protect from light, in a place inaccessible to children.

Incompatibilities.

Zuclopenthixol acetate should only be mixed with zuclopenthixol decanoate, which is also dissolved in medium-chain triglycerides (European Pharmacopoeia).

Zuclopenthixol acetate must not be mixed with depot formulations containing sesame oil, as their mixture alters the pharmacokinetic properties of these products.

Packaging. 10 ampoules of 1 ml in a cardboard box.

Prescription category. Prescription only.

Manufacturer. H. Lundbeck A/S / H. Lundbeck A/S.

Manufacturer's address.
Ottiliavej 9, 2500 Valby, Denmark / Ottiliavej 9, 2500 Valby, Denmark.