Zuclopenthixol Acetate

Registered South African indications:

• Acute psychoses

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Acute alcohol, barbiturate and opiate intoxications
• Comatose states
• Children

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Circulatory collapse
• Depressed level of consciousness due to any cause (e.g. intoxication with alcohol, barbiturates or opiates)
• Coma

Cautions

South African recommendations

• Pregnancy
• Breastfeeding
• Females and males reproductive potential
• Renal impairment
  - Renal disease
• Hepatic impairment
  - Advanced hepatic disease
• Elderly
  - Risk factors for stroke
  - Treatment of dementia with antipsychotics
• Seizure disorders
• Cardiovascular disease
• Diabetic patients (See additional prescribing points)
• Patients susceptible to QT prolongation
   - Hypokalaemia
  - Hypomagnesaemia 
  - Genetic predisposition
• History of cardiovascular disorders
  - QT prolongation
  - Significant bradycardia (<50 beats per minute)
  - Recent acute myocardial infarction
  - Uncompensated heart failure
  - Cardiac dysrhythmia
• Risk factors for venous thromboembolism (VTE)
• Dementia-related behavioural disturbances
• May impair ability to drive and operate machinery  

Recommendations in other jurisdictions

• Hypersensitivity to thioxanthenes or other antipsychotics
• Pregnancy
• Breastfeeding
• Females and males reproductive potential
• Renal impairment
  - Renal failure
• Hepatic impairment
  - Hepatic disease (including advanced hepatic disease)
• Elderly
  - Risk factors for stroke
  - Treatment of dementia with antipsychotics
• Severe respiratory disease
• Epilepsy
  - Conditions predisposing to epilepsy, e.g. alcohol withdrawal or brain damage
• Parkinson's disease
• Narrow-angle glaucoma
• Prostatic hypertrophy
• Hypothyroidism
• Hyperthyroidism
• Myasthenia gravis
• Phaeochromocytoma
• Pre-existing organic brain syndrome
• Pre-existing mental retardation
• Opiate abuse 
• Alcohol abuse 
• Signs of persistent infection
• Cardiovascular disease
• Cardiac disease or arrhythmias
• Persistently prolonged QT intervals
• Patients susceptible to QT prolongation
   - Hypokalaemia
  - Hypomagnesaemia 
  - Genetic predisposition
• History of cardiovascular disorders
  - QT prolongation
  - Significant bradycardia (<50 beats per minute)
  - Recent acute myocardial infarction
  - Uncompensated heart failure
  - Cardiac dysrhythmia
• Risk factors for venous thromboembolism (VTE)
• Abrupt withdrawal
• Diabetic patients (See additional prescribing points)
• Dementia-related behavioural disturbances
• May impair ability to drive and operate machinery  

Forms avail. in SA and covered in this monograph: inj

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Acute psychoses
- Initial treatment of acute psychoses, including mania, exacerbations of chronic psychoses

• IM: 50-150mg (1-3ml): Repeat dose every 2-3 days if necessary

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Dosage should be individually adjusted according to the patient’s condition

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In a few patients, an additional injection may be needed 24-48 hours following the first injection

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In the maintenance therapy, treatment should be continued with zuclopenthixol decanoate

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Coadministered with the last injection of zuclopenthixol acetate, maintenance treatment with zuclopenthixol decanoate: IM: 200-400mg (1-2ml); Repeat at intervals of 2 weeks

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Maintenance treatment with zuclopenthixol decanoate: Higher doses or shorter intervals may be needed

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Indications and dosages registered in other jurisdictions

Acute psychoses
- Initial treatment of acute psychoses including mania and exacerbation of chronic psychoses, particularly where duration of effect of 2-3 days is desirable

• IM: 50-150mg (1-3ml): Repeat dose every 2-3 days if necessary; Max treatment duration: 2 weeks; Max accumulated dosage: 400mg; Max number of injections: 4

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Dosage should be adjusted according to the severity of the patient's illness

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Some patients may need an additional injection between 1-2 days after the first injection. Zuclopenthixol acetate is not intended for long-term use

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Method of administration: Deep intramuscular injection into the upper outer buttock or lateral thigh. Injection volumes >2ml should be distributed between two injection sites

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As with all oil-based injections it is important to ensure, by aspiration before injection, that inadvertent intravascular entry does not occur

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Maintenance therapy: Zuclopenthixol acetate is not intended for long-term use. A single injection of zuclopenthixol acetate has an onset of sedative action shortly after injection and an antipsychotic action persisting for 2-3 days. In this period, maintenance treatment with tablets or a longer acting depot neuroleptic can be initiated. The possible side-effects of long-term maintenance treatment with a neuroleptic, including tardive dyskinesia, should be considered

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Maintenance treatment where required can be continued with zuclopenthixol dihydrochloride or zuclopenthixol decanoate

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Zuclopenthixol dihydrochloride: Oral: Initial: 20-60mg/day, in divided doses 2-3 days after last injection of zuclopenthixol acetate; If necessary titrate by 10-20mg/day; Max: 150mg/24hrs
OR
Coadministered with the last injection of zuclopenthixol acetate, maintenance treatment with zuclopenthixol decanoate: IM: 200-400mg; Repeat at intervals of 2 weeks

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Maintenance treatment with zuclopenthixol decanoate: Higher doses or shorter intervals may be needed

Not established for use in children (South African recommendations)
Not recommended for children (Recommendations in other jurisdictions)

Pregnancy

South African recommendations 

• Caution; not recommended
• Zuclopenthixol acetate should not be administered during pregnancy
• Neonates exposed to zuclopenthixol acetate during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully

Central Nervous System Disorders 

• Insomnia
• Depression
• Anxiety
• Nervousness
• Abnormal dreams
• Agitation
• Decreased libido
• Increased libido 
• Apathy
• Nightmare
• Confusional state
• Somnolence
• Akathisia
• Hyperkinesia
• Hypokinesia
• Tremor
• Dystonia
• Hypertonia
• Headache
• Paraesthesia
• Dizziness
• Disturbances in attention
• Amnesia
• Abnormal gait
• Hyperreflexia
• Tardive dyskinesia
• Dyskinesia
• Parkinsonism
• Syncope
• Ataxia
• Speech disorder
• Seizure 
• Hypotonia
• Migraine
• Neuroleptic malignant syndrome
• Fatigue

Cardiovascular Disorders 

• Tachycardia
• Palpitations
• Prolonged QT electrocardiogram
• Hypotension
• Ventricular arrhythmias
• Ventricular fibrillation
• Ventricular tachycardia
• Torsade de Pointes

Respiratory Disorders

• Dyspnoea
• Nasal congestion

Gastrointestinal Disorders 

• Dry mouth
• Salivary hypersecretion
• Constipation
• Nausea and vomiting
• Dyspepsia
• Diarrhoea
• Abdominal pain
• Flatulence

Hepatobiliary Disorders 

• Abnormal hepatic function
• Jaundice
• Cholestatic hepatitis

Genitourinary Disorders 

• Micturition disorder
• Urinary retention
• Polyuria
• Ejaculation failure
• Erectile dysfunction
• Gynaecomastia
• Galactorrhoea
• Amenorrhoea
• Female orgasmic disorder
• Vulvovaginal dryness
• Priapism

Endocrine and Metabolic Disorders 

• Hyperprolactinaemia
• Increased appetite
• Decreased appetite
• Increased weight
• Decreased weight
• Hyperglycaemia
• Impaired glucose tolerance 
• Hyperlipidaemia

Musculoskeletal Disorders 

• Myalgia
• Muscle rigidity
• Trismus
• Torticollis

Skin and Subcutaneous Tissue Disorders 

• Hyperhidrosis
• Pruritus
• Rash
• Photosensitivity reaction
• Dermatitis
• Pigmentation disorder
• Seborrhoea
• Purpura
• Injection site reaction

Immune, Blood and Lymphatic System Disorders

• Hypersensitivity
• Anaphylactic reaction
• Venous thromboembolism
  - Pulmonary embolism
  - Deep vein thrombosis
• Thrombocytopenia
• Neutropenia
• Leukopenia
• Agranulocytosis
• Hypothermia
• Pyrexia

Sensory Disorders

• Accommodation disorder
• Abnormal vision
• Oculogyration
• Mydriasis
• Vertigo
• Hyperacusis
• Tinnitus

Others

• Pain
• Thirst
• Hot flush
• Withdrawal symptoms
  - Nausea and vomiting
  - Anorexia
  - Diarrhoea
  - Rhinorrhoea
  - Sweating
  - Myalgias
  - Paraesthesias
  - Insomnia
  - Restlessness
  - Anxiety
  - Agitation
  - Vertigo
  - Alternate feelings of warmth and coldness
  - Tremor
• Neonatal drug withdrawal syndrome 
  - Extrapyramidal and/or withdrawal symptoms
  - Agitation
  - Hypertonia
  - Hypotonia
  - Tremor
  - Somnolence
  - Respiratory distress
  - Feeding disorder

• Opiates
• Barbiturates
• Other antipsychotics
• Central nervous system depressants
• General anaesthetics
• Anticoagulants
• Atropine
• Neuromuscular blockers 
• Anticholinergics 
• Metoclopramide
• Piperazine
• Antiparkinson agents
• Lithium
• Sibutramine
• Corticosteroids
• Digoxin
• Vasodilators
• Hydralazine
• Alpha-blockers
• Doxazosin
• Methyldopa
• QT-prolonging agents
• Class Ia and III antiarrhythmics
• Quinidine
• Amiodarone
• Sotalol
• Dofetilide
• Thioridazine
• Macrolides
• Erythromycin 
• Antihistamines
• Quinolone antibiotics
• Moxifloxacin
• Cisapride
• Agents known to cause electrolyte disturbances
• Thiazide diuretics
• Agents known to increase the plasma concentration of zuclopenthixol
• Adrenaline
• Sympathomimetics
• Guanethidine
• Adrenergic-blocking agents
• Adrenergic agents
• Levodopa
• Antiepileptics
• Tricyclic antidepressants 
• CYP2D6 enzyme inhibitors 

Other interactions

• Alcohol

• Mental status
• Vital signs
• Weight
• Height
• Body mass index (BMI)
• Waist circumference
• Full blood count
• Electrolytes 
• Hepatic function
• Blood glucose (fasting plasma glucose level)
• HbA1c
• Lipid panel
• Ophthalmic examination

Specific cases may require

• Electrocardiogram (ECG) (patients with a history of QT prolongation, other cardiovascular disorders or electrolyte disturbances)

Additional observations

• Changes in menstruation
• Changes in libido
• Development of galactorrhea
• Erectile and ejaculatory function
• Abnormal involuntary movements
• Parkinsonian signs
• Tardive dyskinesia 
• Visual changes 
• Fall risk

Neuroleptic malignant syndrome 

• Symptoms may be: hyperthermia, muscle rigidity, fluctuating consciousness, instability of the autonomous nervous system
• The risk is possibly greater with the more potent agents. Patients with pre-existing organic brain syndrome, mental retardation and opiate and alcohol abuse are over-represented among fatal cases (Recommendations in other jurisdictions)
• Treatment
  - Discontinuation of zuclopenthixol acetate
  - Symptomatic treatment and use of general supportive measures
  - Dantrolene and bromocriptine may be helpful
• Symptoms may persist for more than a week after oral neuroleptics are discontinued and somewhat longer when associated with the depot forms of the agents

Diabetic patients

• Zuclopenthixol acetate may modify insulin and glucose responses calling for adjustment of the antidiabetic therapy in diabetic patients

Zuclopenthixol is a potent neuroleptic of the thioxanthene series with a piperazine side-chain. The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking effect. The thioxanthenes have a high affinity for both the adenylate cyclase coupled dopamine D₁ receptors and for the dopamine D₂ receptors; in the phenothiazine group the affinity for D₁ receptors is much lower than that for D₂ receptors, whereas butyrophenones, diphenylbutylpiperidines and benzamides only have affinity for D₂ receptors. In the traditional tests for antipsychotic effect, e.g. antagonism of stereotypic behaviour induced by dopamine agonists, the chemical groups of neuroleptics mentioned reveal equal but dosage dependent activity. However, the antistereotypic effect of phenothiazines, butyrophenones, diphenylbutylpiperidines, and benzamides is strongly counteracted by the anticholinergic drug, scopolamine, while the antistereotypic effect of the thioxanthenes, e.g. zuclopenthixol, is not, or only very slightly, influenced by concomitant treatment with anticholinergics.

Injection (per ml) 50mg

• Clopixol Acuphase 50mg/ml (H. Lundbeck) originator