Zuclopenthixol Acetate (Clopixol Acuphase)

1. Health Canada Product Monograph — Zuclopenthixol Acetate

• Zuclopenthixol acetate (Clopixol Acuphase) is used for the initial treatment of acute psychotic episodes or exacerbations of psychosis in schizophrenia, when reliable use of oral medication cannot be assured.
• It is not intended for long-term treatment; once the acute episode is controlled, ongoing therapy is continued with oral Clopixol tablets or, for maintenance, the long-acting Clopixol Depot injection.

• The safe use of zuclopenthixol during pregnancy has not been established.
• Zuclopenthixol was not teratogenic in rats or rabbits, but increased stillbirths, reduced pup survival, and delayed pup development were seen in animal studies, and the clinical significance of these findings is unclear.
• Zuclopenthixol is known to cross the placenta.
• Babies exposed to zuclopenthixol during the third trimester are at risk of withdrawal or movement symptoms after birth, including agitation, abnormal muscle tone, tremor, sleepiness, breathing difficulty, and feeding problems.
• Zuclopenthixol acetate should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

• Zuclopenthixol passes into human breast milk, with an average milk-to-serum concentration ratio of about 0.3.
• The safe use of zuclopenthixol during breastfeeding has not been established.

• The pharmacokinetics, safety, and effectiveness of zuclopenthixol in geriatric patients with schizophrenia have not been systematically studied, so caution is needed in dose selection given the more frequent liver, kidney, and heart problems in this age group.
• Zuclopenthixol acetate is not approved for treating older adults with dementia-related psychosis, because antipsychotic drugs increase the risk of death in this population.
• Older adults with dementia treated with antipsychotics also have an increased risk of stroke and other cerebrovascular events compared with placebo.

• The safety and effectiveness of zuclopenthixol acetate in patients under 18 years of age have not been established, and Health Canada has not authorized a pediatric indication.

• The usual dose is 50 to 150 mg (1 to 3 mL) given by intramuscular injection, repeated if necessary at intervals of 2 to 3 days; some patients need an extra injection 1 to 2 days after the first.
• Onset of action is within 2 to 4 hours, with a duration of effect of 2 to 3 days from a single injection; peak blood levels are reached, on average, 24 to 48 hours after injection, so close supervision is needed to avoid over- or under-treatment during this delay.
• Treatment is not intended to exceed 2 weeks: the maximum cumulative dose is 400 mg and the number of injections should not exceed four.
• The injection is given by deep intramuscular injection into the buttock; volumes greater than 2 mL are split between two injection sites.
• For patients needing both acute and maintenance treatment, Clopixol Acuphase can be mixed in the same syringe with Clopixol Depot and given as one co-injection, but it cannot be mixed with other long-acting antipsychotic depot products.
• After treatment with Clopixol Acuphase, oral Clopixol is usually started 2 to 3 days after the last injection, or Clopixol Depot maintenance therapy can be started concurrently with the last Acuphase injection, using dose conversion guidelines.
• If a dose is missed, it should be given as soon as possible, and the following dose given at the usual interval after that.
• Zuclopenthixol has not been specifically studied in patients with impaired liver or kidney function, so caution is needed in dose selection.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Overdose can cause severe drowsiness progressing to coma.
• Extrapyramidal symptoms (abnormal, involuntary movements) and convulsions may occur.
• Cardiovascular effects can include low blood pressure, circulatory shock, abnormal heart rhythms (including QT prolongation and Torsade de Pointes), and cardiac arrest.
• Body temperature regulation may be disrupted, leading to abnormally high or low body temperature.
• There is no specific antidote; treatment is symptomatic and supportive, with a focus on maintaining breathing and circulation.
• Low blood pressure should be managed with IV fluids; epinephrine (adrenaline) should be avoided, as it may worsen hypotension.
• Severe extrapyramidal reactions may be treated with antiparkinsonian medication.

• Dry mouth is very common.
• Muscle stiffness (hypertonia) is very common.
• Marked sedation is expected within 2 hours of injection, usually peaking around 8 hours, and is part of the intended calming effect; tolerance to this sedative effect may develop with repeated injections.
• Restlessness or an inability to sit still (akathisia) is common.
• Reduced spontaneous movement (hypokinesia) is common.
• Tremor is common.
• Dizziness is common.
• Abnormal muscle spasms or postures (dystonia) are common.
• Blurred vision or other visual accommodation problems are common.
• A fast heart rate (tachycardia) is common.
• Excess saliva production is common.
• Insomnia, anxiety, or agitation may occur.
• Headache may occur.
• Nausea or vomiting may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Neuroleptic malignant syndrome, a rare but potentially fatal reaction with high fever, muscle rigidity, altered consciousness, and unstable blood pressure or heart rate, can occur.
• Geriatric patients with dementia treated with zuclopenthixol have an increased risk of death compared with placebo.
• Tardive dyskinesia, a potentially irreversible movement disorder with repetitive, involuntary movements of the face, tongue, or limbs, can develop.
• QT interval prolongation and, rarely, serious heart rhythm disturbances including Torsade de Pointes, ventricular arrhythmias, and sudden unexplained death have been reported.
• An increased risk of stroke and other cerebrovascular events has been seen with antipsychotics in older patients with dementia.
• Because peak blood levels are not reached for 24 to 48 hours after injection, over-sedation or excessive drug effect can build up gradually and requires close monitoring, especially after repeat injections.
• Blood cell disorders, including low white blood cell counts, low platelet counts, and agranulocytosis, have been reported.
• Venous thromboembolism (blood clots in the veins) has been reported with antipsychotic drugs.
• Rhabdomyolysis (breakdown of muscle tissue) has been reported, sometimes with serious complications.
• High blood sugar and diabetic ketoacidosis have occurred, sometimes with no prior history of blood sugar problems.
• Elevated prolactin levels can cause menstrual changes, unexpected milk production, and, with long-term elevation, reduced bone density.
• Priapism (a prolonged, painful erection) has been reported rarely.
• Zuclopenthixol can lower the seizure threshold and may trigger convulsions.
• Difficulty swallowing can occur and may lead to choking or aspiration pneumonia.
• Liver problems, including cholestatic hepatitis and jaundice, have been reported.
• Serious allergic reactions, including anaphylaxis, have been reported.
• Babies exposed in the womb during the third trimester can develop withdrawal or movement symptoms after birth.
• Seek urgent medical attention for high fever with muscle stiffness, a very slow or irregular heartbeat, fainting, sudden one-sided weakness or vision change, difficulty swallowing or breathing, or excessive unresponsive sedation.

• Use with caution in patients with cardiovascular disease or risk factors for abnormal heart conduction.
• Use with caution in patients at risk of QT prolongation, including those with low potassium or magnesium, significant bradycardia, a recent heart attack, heart failure, or a personal history of arrhythmia.
• Use with caution in patients with Parkinson's disease, since zuclopenthixol can worsen motor symptoms.
• Use with caution in patients with a history of seizures.
• Use with caution in patients with diabetes; blood glucose and body weight should be monitored at baseline and periodically.
• Use with caution in patients with impaired liver function.
• Use with caution in patients with impaired kidney function.
• Use with caution in older adults generally, given more frequent age-related organ dysfunction.
• Avoid use in patients with known or suspected narrow-angle glaucoma.
• Use with caution in patients with previously detected breast cancer, since prolactin can stimulate the growth of some breast tumours.
• Use with caution in patients with risk factors for blood clots.
• Close supervision is required during the period after each injection, since the delayed and prolonged drug release can cause over-medication or insufficient symptom control if not monitored.
• Complete blood counts should be checked before starting treatment and periodically afterward.
• Caution should be used around driving or operating machinery because of significant sedation, particularly in the hours after each injection.

• Contraindicated during acute intoxication with alcohol, barbiturates, or opiates.
• Contraindicated in central nervous system depression from any cause, coma, suspected or confirmed subcortical brain damage, or circulatory collapse.
• Contraindicated in patients with known hypersensitivity to zuclopenthixol, other thioxanthenes, or any ingredient in the formulation.

• Combining zuclopenthixol with alcohol, barbiturates, or other central nervous system depressants increases sedation; high doses of hypnotic drugs should be avoided together with zuclopenthixol.
• Zuclopenthixol may block the blood-pressure-lowering effect of adrenergic antagonists and similar drugs; concurrent use should be avoided.
• Zuclopenthixol may add to the effects of other anticholinergic medications.
• Other antipsychotics and tricyclic antidepressants may mutually interfere with each other's breakdown by the liver, raising blood levels of either drug.
• Metoclopramide increases the risk of movement-related (extrapyramidal) side effects when combined with zuclopenthixol.
• Zuclopenthixol may reduce the effect of levodopa and other dopamine agonist medications.
• Drugs that inhibit the liver enzyme CYP2D6 can decrease the clearance of zuclopenthixol and increase the risk of QT prolongation and dangerous heart rhythms.
• Combining zuclopenthixol with other drugs that suppress bone marrow function increases the risk of blood cell suppression, and this is especially relevant for long-acting depot formulations that cannot be quickly removed from the body.
• Co-administration with other drugs known to significantly increase the QT interval, including certain antiarrhythmics, some antipsychotics, some macrolide antibiotics, some quinolone antibiotics, and lithium, should be avoided.
• Thiazide diuretics can cause low potassium, which increases the risk of QT prolongation and dangerous heart rhythms when combined with zuclopenthixol.

• Not applicable: Clopixol Acuphase is given by intramuscular injection, so food intake does not affect this medication.

• Given by a healthcare professional as an intramuscular injection, repeated no more often than every 2 to 3 days as needed; timing is not linked to meals.
• Because peak effect is delayed for 24 to 48 hours after each injection, patients are monitored closely during this window rather than at a fixed time of day.

• Store single-dose ampoules between 15°C and 25°C, protected from light; discard any unused portion after opening.

• Zuclopenthixol acetate (Clopixol Acuphase) is a short-acting antipsychotic injection given by a healthcare professional to control acute psychotic episodes.
• It is not intended for long-term use; treatment is limited to a maximum of four injections over up to two weeks, after which therapy continues with oral tablets or a long-acting depot injection.
• Its effect builds up gradually over 1 to 2 days after each injection, so you will be monitored closely during this period.
• Report severe constipation, unusual new movements, or signs of high fever and muscle stiffness to a doctor right away.
• Seek urgent medical attention for fainting, a very irregular heartbeat, sudden weakness or vision changes, or difficulty swallowing or breathing.