Zuclopenthixol Dihydrochloride

Registered South African indications:

• Symptoms of restlessness, agitation, hostility, aggression, psychomotor excitement and other behavioural disturbances in acute and chronic schizophrenia, manic phase of bipolar affective disorder and mental retardation

Contraindications

South African recommendations

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

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 of reproductive potential
• Renal impairment
  - Renal disease
• Hepatic impairment
  - Advanced hepatic disease
• Elderly
  - Risk factors for stroke
  - Treatment of dementia with antipsychotics
• Prolonged use
• Seizure disorders
• Cardiovascular disease
• Diabetes mellitus (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
• Hydrogenated castor oil sensitivity
• Galactose intolerance e.g galactosaemia
• Lapp lactase deficiency 
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• Hypersensitivity to thioxanthenes or other antipsychotics
• Pregnancy
• Breastfeeding
• Females and males of 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
• 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
• Hydrogenated castor oil sensitivity
• Galactose intolerance e.g galactosaemia
• Total lactase deficiency 
• Glucose-galactose malabsorption
• May impair ability to drive and operate machinery  

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

Dosages below include:

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

South African registered indications and dosages

Symptoms of restlessness, agitation, hostility, aggression, psychomotor excitement and other behavioural disturbances in:
Acute schizophrenia and other acute psychoses
Severe acute states of agitation
Mania

• Oral: (tab): Usual dose: 10-50mg, dly

Moderate to severe

• Oral: (tab): Initial: 20mg, dly; Titrate by 10-20mg/day at intervals of 2-3 days, if necessary; Max: 75mg

Chronic schizophrenia and other chronic psychoses

• Oral: (tab): Maintenance: 20-40mg, dly

Agitation in oligophrenic patients

• Oral: (tab): 6-20mg, dly; Titrate if necessary by 25-40mg, dly

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Dosage should be individually adjusted according to the condition. In general, small doses should be used initially and increased to the optimal effective level as rapidly as possible based on therapeutic responses. The maintenance dose can usually be given as a single dose at bedtime

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Indications and dosages registered in other jurisdictions

Psychoses
- Especially schizophrenia

• Oral: (fct): Initial: 20-30mg/day (sometimes with higher dosage requirements in acute cases), increasing as necessary; Maintenance: 20-50mg/day: Max single dose: 40mg

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Dosage range is 4-150mg/day in divided doses

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When transferring patients from oral to depot antipsychotic treatment, the oral medication should not be discontinued immediately, but gradually withdrawn over a period of several days after administering the first injection

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Method of administration: The tablets are swallowed with water

Not recommended for children (South African recommendations)
Not indicated for use in children (International manufacturer recommendations)

Pregnancy

South African recommendations 

• Caution; not recommended
• Zuclopenthixol dihydrochloride should not be administered during pregnancy
• Neonates exposed to zuclopenthixol dihydrochloride 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

Recommendations in other jurisdictions

• Caution; not recommended
• Zuclopenthixol should not be administered during pregnancy unless the expected benefit to the patient outweighs the theoretical risk to the foetus
• Neonates exposed to antipsychotics (including zuclopenthixol) 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
• Animal studies have shown reproductive toxicity

Breastfeeding

South African recommendations 

• Caution; not recommended 
• Zuclopenthixol is excreted into breast milk. Mothers on zuclopenthixol dihydrochloride therapy should not breastfeed their babies

Recommendations in other jurisdictions

• Caution 
• As zuclopenthixol is found in breast milk in low concentrations it is not likely to affect the infant when therapeutic doses are used. The dose ingested by the infant is <1% of the weight-related maternal dose (in mg/kg). Breastfeeding can be continued during zuclopenthixol therapy if considered of clinical importance, but observation of the infant is recommended, particularly in the first 4 weeks after giving birth

Fertility

• In humans, adverse events such as hyperprolactinaemia, galactorrhoea, amenorrhoea, erectile dysfunction and ejaculation failure have been reported. These events may have a negative impact on female and/or male sexual function and fertility. If clinical significant hyperprolactinaemia, galactorrhoea, amenorrhoea or sexual dysfunctions occur, a dose reduction (if possible) or discontinuation should be considered. The effects are reversible on discontinuation. Administration of zuclopenthixol to male and female rats were associated with a slight delay in mating. In an experiment where zuclopenthixol was administered via the diet, impaired mating performance and reduced conception rate was noted

Renal Impairment

South African recommendations 

• Caution; no dose adjustment recommended 

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended 
  Zuclopenthixol dihydrochloride can be given in usual doses to patients with reduced renal function
• Renal failure: Caution; dose adjustment recommended 
  Dosage should be reduced to half the normal dosage

Hepatic Impairment

South African recommendations 

• Caution; no dose adjustment recommended 

Recommendations in other jurisdictions

• Caution; dose adjustment recommended 
  Patients with compromised hepatic function should receive half the recommended dosages. Serum-level monitoring is advised
  Use with caution in patients with liver disease

Elderly

South African recommendations 

• Caution; no dose adjustment recommended 
  Older patients should receive dosages in the lower end of the dosage range

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  In accordance with standard medical practice, initial dosage may need to be reduced to a quarter or half the normal starting dose in frail or older patients
  Older people require close supervision because they are especially prone to experience such adverse effects as sedation, hypotension, confusion, and temperature changes

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

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 
• Migraine
• Hypotonia
• 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

Immune, Blood and Lymphatic System Disorders

• Venous thromboemoblism
  - Pulmonary embolism
  - Deep vein thrombosis
• Thrombocytopenia
• Neutropenia
• Leukopenia
• Agranulocytosis
• Hypersensitivity
• Anaphylactic reaction
• 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
• 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
• Lithium
• 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

The action of zuclopenthixol, as with other antipsychotics is mediated through dopamine receptor blockage. Zuclopenthixol has a high affinity for D₁ and D₂ receptors and activity has been demonstrated in standard animal models used to assess antipsychotic action. Serotonergic blocking properties, a high affinity for alpha-adrenoreceptors and slight antihistamine properties have been observed.

 

Tablet 2mg 

• Clopixol tablets 2mg (H.Lundbeck) originator

Tablet 10mg 

• Clopixol tablets 10mg (H.Lundbeck) originator