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Zuclopenthixol is a neuroleptic from the thioxanthene group.
The antipsychotic effect of neuroleptics is associated with the blockade of dopamine receptors, and also with the possible involvement of 5HT-receptor blockade. In vitro, zuclopenthixol has high affinity for both dopamine D1- and D2-receptors, α1-adrenoceptors and 5HT2-receptors (5-hydroxytryptamine), but has no affinity for cholinergic muscarinic receptors. It has a weak affinity for histamine (H1) receptors and does not have a blocking effect on α2-adrenoceptors.
In vivo, the affinity for D2 binding sites dominates over the affinity for D1 receptors. Zuclopenthixol is a potent neuroleptic, as demonstrated by all behavioral studies of neuroleptic activity (the ability to block dopamine receptors). At average daily dosage and oral use for antipsychotic treatment, affinity for blocking sites binding the dopamine D2 receptor is observed in in vitro and in vivo models.
Like most other neuroleptics, zuclopenthixol increases serum prolactin levels.
Pharmacological studies have clearly demonstrated that the oily solution of zuclopenthixol decanoate exhibits a long-lasting neuroleptic effect, and the amount of drug required to maintain a constant effect over a long period is significantly lower with the depot formulation than with daily oral administration of zuclopenthixol. From a clinical application perspective, the pharmacological data may suggest that a long-lasting neuroleptic effect without overt sedation can be achieved with the depot formulation. Furthermore, the risk of interactions with anesthetics can be expected to be low.
Clinical efficacy and safety
In clinical use, zuclopenthixol decanoate is indicated for the maintenance treatment of patients with chronic psychotic disorders. Positive results have also been obtained in the treatment of hyperactive and aggressive patients with mental retardation.
The specific inhibitory effect of zuclopenthixol decanoate makes it suitable for use in the treatment of psychotic patients with symptoms of agitation, restlessness, hostility, and aggressiveness.
Zuclopenthixol decanoate exhibits a transient dose-dependent sedative effect. However, if the patient changes maintenance therapy to zuclopenthixol decanoate from oral zuclopenthixol or from injectable zuclopenthixol acetate, the risk of sedation is reduced. Tolerance to the nonspecific sedative effect develops rapidly.
Zuclopenthixol decanoate is particularly effective in the treatment of agitated, restless, hostile or aggressive patients.
Zuclopenthixol decanoate provides the possibility of continuous treatment, which is extremely important for patients who do not comply with the doctor's prescription for taking zuclopenthixol orally. Zuclopenthixol decanoate prevents the development of frequent relapses, which are associated with the interruption of oral medication by patients.
Pharmacokinetics.
Absorption
By esterification of zuclopenthixol with decanoic acid, zuclopenthixol is converted into a highly lipophilic substance, zuclopenthixol decanoate. When dissolved in oil and administered intramuscularly, the ester diffuses rather slowly from the oil to the aqueous phase of the body, after which it is rapidly hydrolyzed, releasing the active zuclopenthixol.
The maximum serum concentration is reached 3–7 days after injection.
The half-life after intramuscular injection is 3 weeks (reflecting release from the depot), and steady-state concentrations are achieved with repeated administration within 3 months.
Distribution
The apparent volume of distribution (Vd) β is approximately 20 l/kg.
Plasma protein binding is approximately 98–99%.
Biotransformation
The metabolism of zuclopenthixol occurs via three main pathways: sulfoxidation, N-dealkylation of the side chain, and conjugation with glucuronic acid. The metabolites have no psychopharmacological activity. The pharmacological action of unmetabolized zuclopenthixol prevails over the effects of its metabolites on the brain and other tissues due to the fact that the metabolites of zuclopenthixol have no neuroleptic activity.
Selection
The elimination half-life (t1/2β) of zuclopenthixol is approximately 20 hours, and the systemic clearance (Cls) is approximately 0.86 l/min.
Metabolites have no neuroleptic activity and are excreted mainly in the feces and partially in the urine (10%).
The average ratio of the concentration of the active substance in breast milk of women to the concentration of the active substance in the blood serum of women was about 0.29 on the eve of the next dose in a stable regimen of continuous therapy with zuclopenthixol orally or intramuscularly in the form of decanoate.
Linearity
The kinetics are linear. When 200 mg of zuclopenthixol decanoate was administered every 2 weeks, the mean minimum steady-state level was approximately 10 ng/mL (25 nmol/L).
Elderly patients
Pharmacokinetic parameters significantly depend on the patient's age.
Kidney dysfunction
Given the above elimination characteristics, it can be assumed that decreased renal function is unlikely to have a major effect on the serum levels of the drug.
Liver dysfunction
No data.
Polymorphism
An in vivo study showed that some of the metabolic pathways are subject to genetic polymorphisms in sparteine/debrisoquine oxidation (CYP2D6).
Pharmacokinetic/pharmacodynamic interactions
A serum (plasma) concentration before the next administration of 2.8–12 ng/mL (7–30 nmol/L) with a maximum-minimum fluctuation of less than 2.5 is recommended for maintenance treatment of patients with moderate schizophrenia.
Pharmacokinetically, a dose of zuclopenthixol decanoate 200 mg once every 2 weeks or 400 mg once every 4 weeks is equivalent to a daily oral dose of 25 mg of Clopixol.
Indication
Supportive therapy of schizophrenia and other psychoses, especially with symptoms such as hallucinations, mania and thought disorders with agitation, restlessness, hostility and aggression.
Contraindication
Hypersensitivity to any component of the drug. Circulatory collapse, depression of consciousness of any origin (for example, as a result of alcohol, barbiturate or opioid intoxication), coma.
Interaction with other medicinal products and other types of interactions
Combinations requiring precautions for use
Zuclopenthixol decanoate may enhance the sedative effects of alcohol, barbiturates and central nervous system inhibitors.
Neuroleptics may enhance or reduce the effect of antihypertensive agents; the hypotensive effect of guanethidine and similarly acting agents is weakened.
Zuclopenthixol may potentiate the effects of general anesthetics and anticoagulants and prolong the duration of action of neuromuscular blocking agents.
The anticholinergic effects of atropine or other drugs with anticholinergic properties may be enhanced.
Concomitant use of neuroleptics, lithium, or sibutramine increases the risk of neurotoxicity.
Tricyclic antidepressants and neuroleptics mutually inhibit each other's metabolism and may worsen diabetes control.
Zuclopenthixol decanoate may reduce the effectiveness of levodopa, adrenergic and anticonvulsants, and the combination with metoclopramide, piperazine and 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 antihypertensive agents of the vasodilator group, such as hydralazine, and α-blockers (e.g. doxazosin) or methyldopa may be enhanced.
The concomitant use of zuclopenthixol and medicinal products known to prolong the QT interval or induce cardiac arrhythmias, such as tricyclic antidepressants or other antipsychotics, should be avoided.
Since zuclopenthixol is partially metabolized by CYP2D6, concomitant use of drugs that can inhibit this enzyme may inhibit the elimination of zuclopenthixol.
The increase in QT interval associated with the use of antipsychotics may be enhanced by concomitant use with other drugs that can significantly prolong the QT interval. Combinations with such drugs should be avoided as:
Class Ia and III antiarrhythmics (e.g. quinidine, amiodarone, sotalol, dofetilide).
Some antipsychotics (e.g. thioridazine).
Some macrolide antibiotics (such as erythromycin).
Some antihistamines (e.g. terfenadine, astemizole).
Some quinolone antibiotics (e.g. gatifloxacin, moxifloxacin).
The list above is not exhaustive, and 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 zuclopenthixol concentrations should also be used with caution as they may increase the risk of QT prolongation and malignant arrhythmias.
Antipsychotics may antagonize the effects of adrenaline and other sympathomimetics and neutralize the antihypertensive effects of guanethidine and similar adrenoblocking agents.
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.
Acute withdrawal symptoms, including nausea, vomiting, sweating and insomnia, have been reported after abrupt discontinuation of antipsychotics. In addition, relapse of psychotic symptoms may occur, and involuntary movement disorders (such as akathisia, dystonia and dyskinesia) have been reported.
Plasma concentrations of zuclopenthixol decanoate gradually decrease over several weeks, making gradual withdrawal of the drug with a stepwise dose reduction unnecessary.
When switching patients from oral antipsychotics to depot antipsychotics, the oral drug should not be withdrawn abruptly; it should be withdrawn gradually over several days after the first depot injection.
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 multiple agents. Fatal cases occur mainly in patients with an existing organic syndrome, mental retardation, opiate and alcohol abuse.
Treatment: discontinuation of neuroleptics, 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 using depot forms of the drugs.
As with other neuroleptics, zuclopenthixol decanoate should be used with caution in the treatment of patients with organic brain syndrome, seizures and progressive liver disease.
Rare cases of abnormal blood counts have been reported. If the patient develops signs of persistent infection, complete blood counts should be performed.
Like other antipsychotics, zuclopenthixol decanoate may alter insulin requirements and glucose tolerance, 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 agents belonging to the therapeutic class of antipsychotics, zuclopenthixol decanoate may cause QT prolongation. Existing QT prolongation may increase the risk of malignant arrhythmias. Therefore, zuclopenthixol decanoate should be used with caution in patients with suspected hypokalaemia, hypomagnesaemia 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, decompensated heart failure or cardiac arrhythmias. Concomitant treatment with other antipsychotics should be avoided.
Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. As patients taking antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with zuclopenthixol decanoate 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 events
An approximately three-fold increased risk of cerebrovascular events has been observed in randomized placebo-controlled trials of some atypical antipsychotics in groups of patients with dementia. The mechanism of this increased risk is unknown. An increased risk cannot be excluded for other antipsychotics and other patient populations. Zuclopenthixol decanoate should be used with caution in patients with risk factors for stroke.
Increased mortality in elderly patients with dementia
Clinical trial data suggest that elderly patients with dementia who take antipsychotics have a slightly higher risk of death than patients who do not take these medications. There are insufficient data to determine this risk precisely, and the reason for the increased risk is unknown.
Zuclopenthixol decanoate is not indicated for the treatment of behavioral disorders associated with dementia.
Cases of leukopenia, neutropenia and agranulocytosis have been reported with antipsychotics, including zuclopenthixol decanoate. Long-acting depot forms of antipsychotics should be used with caution in combination with other agents with myelosuppressive potential, as these forms cannot be rapidly eliminated from the body if necessary.
Use during pregnancy or breastfeeding
Pregnancy
Zuclopenthixol decanoate should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the fetus.
Neonates whose mothers have taken antipsychotics (including zuclopenthixol decanoate) during the last trimester of pregnancy may be at risk of adverse reactions, including extrapyramidal symptoms or withdrawal symptoms, which may vary in severity and duration following delivery. Cases of agitation, hypertension, hypotension, tremor, somnolence, respiratory distress or feeding difficulties have been reported. Therefore, neonates should be closely monitored.
Animal studies have shown reproductive toxicity.
Breast-feeding
The drug is found in breast milk in low concentrations, and its effect on the infant is unlikely at therapeutic doses. The dose received by the infant with breast milk is less than 1% of the maternal daily dose and depends on the mother's body weight (mg/kg). Breastfeeding may continue during treatment with zuclopenthixol decanoate if clinically necessary, but medical supervision of the infant is recommended, especially in the first four weeks after birth.
Fertility
Hyperprolactinemia, galactorrhea, amenorrhea, decreased libido, erectile dysfunction and ejaculation failure have been reported (see section 4.8). These events may adversely affect female and/or male sexual function and fertility.
If possible, the dose should be reduced or the drug should be discontinued if clinically significant hyperprolactinemia, galactorrhea, amenorrhea, or sexual dysfunction develops. These disorders resolve after 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, a deterioration in mating performance and a decrease in fertilizing ability were observed.
Ability to influence reaction speed when driving vehicles or other mechanisms
Clopixol Depot is a sedative. Patients who are prescribed psychotropic drugs or after drinking alcohol may experience some decrease in general attention and concentration. They should be warned about the possible effect of the drug on the ability to drive and operate other mechanisms.
Patients should not drive if they experience blurred vision.
Method of administration and doses
Adults
The doses of the drug and the interval between injections are determined individually, according to the patient's condition, in order to achieve maximum control of psychotic symptoms with a minimum of undesirable effects.
For maintenance treatment, the dosage range is usually 200–400 mg (1–2 ml) every 2–4 weeks.
Some patients may require higher doses or shorter intervals between injections. Injections greater than 2 ml should be divided between two injections at different sites.
If the volume exceeds 2–3 mL of a 200 mg/mL solution, a more concentrated solution should be preferred.
When switching from treatment with oral zuclopenthixol or zuclopenthixol acetate to maintenance treatment with zuclopenthixol decanoate, the following regimen should be followed.
1) Switching from oral zuclopenthixol to zuclopenthixol decanoate.
Patients should continue to take zuclopenthixol orally for the first week after the first injection, but at a reduced dose.
2) Switching from zuclopenthixol acetate to zuclopenthixol decanoate.
Simultaneously with the last injection of zuclopenthixol acetate (100 mg), zuclopenthixol decanoate should be administered intramuscularly 200–400 mg (1–2 ml). Repeated injections of zuclopenthixol decanoate should be performed every 2 weeks. If necessary, higher doses can be administered or shorter intervals between injections can be made.
Zuclopenthixol acetate and zuclopenthixol decanoate can be mixed in a syringe and administered as a single injection (co-injection).
When switching from other depot forms to 200 mg zuclopenthixol decanoate, equivalent ratios of 25 mg fluphenazine decanoate, 40 mg cis(Z)-flupenthixol decanoate or 50 mg haloperidol decanoate should be used.
The doses of zuclopenthixol decanoate and the intervals between injections should be adjusted according to the patient's response.
Elderly patients: Lower therapeutic doses should be prescribed.
Renal impairment: Patients with renal impairment should be given the drug in normal doses.
Hepatic impairment: Careful dose titration and, if possible, serum drug levels are recommended.
Clopixol Depot is administered intramuscularly in the upper outer quadrant of the buttock. Injection volumes exceeding 2 ml should be divided between two injections at different sites. Local tolerability is good.
Children
Use in children and adolescents is not recommended due to lack of clinical data.
With simultaneous overdose with drugs that can affect cardiac activity, there have been cases of ECG changes, QT prolongation, torsades de pointes and ventricular arrhythmias, and cardiac arrest.
Treatment
Symptomatic and supportive. Measures should be taken to maintain respiratory and cardiovascular function. Epinephrine should not be used as this may further reduce blood pressure. Convulsions can be treated with diazepam and movement symptoms with biperiden.
Side effects
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 disorders may develop, especially in the first few days after injection and 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 alleviate tardive dyskinesia, but may aggravate it. It is recommended to reduce the dose or, if possible, discontinue treatment with zuclopenthixol. In case of persistent akathisia, the use of a benzodiazepine or propranolol is recommended.
The frequency of 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 unknown.
There have been rare reports of QT prolongation, ventricular arrhythmias: ventricular fibrillation, ventricular tachycardia, cardiac arrest, torsades de pointes and sudden death with the use of medicinal products belonging to the therapeutic class of antipsychotics, including zuclopenthixol decanoate.
Abrupt discontinuation of zuclopenthixol decanoate 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 occur 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. Store in the original package in order to protect from light. Keep out of the reach of children.
Incompatibility
Zuclopenthixol decanoate should only be mixed with zuclopenthixol acetate, which is also soluble in medium chain triglycerides (European Pharmacopoeia).
Zuclopenthixol decanoate should not be mixed with depot forms containing sesame oil, as their mixture alters the pharmacokinetic properties of these agents.
Packaging
10 ampoules of 1 ml 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.
Specifications
Characteristics
Active ingredient
Zuclopenthixol decanoate
Adults
Can
ATC code
N NERVOUS SYSTEM AGENTS; N05 PSYCHOLEPTICS; N05A ANTIPSYCHOTICS; N05A F Thioxanthene derivatives; N05A F05 Zuclopenthixol
Country of manufacture
Denmark
Diabetics
Can
Dosage
200 mg/ml
Drivers
With caution
For allergies
With caution
For children
It is impossible.
Form
Ampoules
Method of application
Long-acting injections
Nursing
It is impossible.
Pregnant
It is impossible.
Primary packaging
ampoule
Producer
H. Lundbeck
Quantity per package
10 ampoules
Trade name
Clopixol
Vacation conditions
By prescription
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