Clozapine

Registered South African indications:

• Schizophrenia
• Drug-induced psychosis in Parkinson's disease

Contraindications

• Hypersensitivity to the active ingredient or any of its excipients 
• Patients unable to undergo regular blood tests 
• History of toxic or idiosyncratic granulocytopenia or agranulocytosis
• History of clozapine-induced agranulocytosis
• Impaired bone marrow function
• Uncontrolled epilepsy
• Alcoholic and other toxic psychoses
• Drug intoxication
• Comatose conditions
• Circulatory collapse 
• Central nervous system depression
• Severe cardiac disorders
• Active or progressive hepatic disease
• Paralytic ileus
• Coadministration with agents with a known potential for causing agranulocytosis
• Coadministration with other depot antipsychotics 

Cautions

• Pregnancy
• Breastfeeding 
• Moderate to severe renal impairment ( <50ml/min/1.73m²)
• Moderate to severe hepatic impairment
• Elderly (≥75 years with/without renal impairment)
• Leukopenia
• Cardiovascular disorders
• Myocardial infarction 
• QT prolongation
• Risk factors for stroke 
• Risk factors for thromboembolism
• Epilepsy
• Prostatic enlargement 
• Narrow angle glaucoma
• Impaired intestinal peristalsis
• History of lower abdominal surgery
• History of colonic disease
• Dementia-related psychosis
• Diabetes mellitus or risk factors thereof 
• Change in smoking habits
• Abrupt withdrawal 
• Galactose intolerance
• Lapp lactase deficiency
• Glucose-galactose malabsorption

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

Schizophrenia - Treatment resistant
Reducing risk of suicidal behaviour in schizophrenia and schizoaffective disorder

• Oral (tab): Initial: Day 1: 12.5mg, 12-24hrly; Day 2: 25-50mg/day, in 1-2 divided doses; Titrate by 25-50mg to achieve dose of 300mg, dly within 2-3 weeks; Maintenance: 300-600mg, in divided doses; Treatment duration: At least 6 months; Max: 900mg/24hrs

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If needed titrate by 50-100mg at intervals of 7 days

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In patients in whom the interval since the last dose exceeds 2 days, treatment should be re-initiated starting at 12.5mg

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Termination should occur over 1-2 week period

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If daily dose is equal to or < 200mg, dose can be taken as a single dose at night

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Drug-induced psychosis in Parkinson's disease

• Oral (tab): Initial: 12.5mg, at night; Titrate by 12.5mg at intervals of at least 4 days; Maintenance: 25-37.5mg, dly; Max: 50mg/24hrs

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Discontinue drug slowly over 1-2 weeks by down-titrating by 12.5mg increments

Not established for use in children younger than 16 years

Pregnancy 

• Caution; no evidence of risk in studies
• For clozapine, there are only limited clinical data on exposed pregnancies. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing to pregnant women
• Neonates exposed to antipsychotics (including clozapine) 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

Breastfeeding

• Caution; not recommended 
• Animal studies suggest that clozapine is excreted in breast milk and has an effect in the breastfeeding infant, therefore, mothers receiving clozapine should not breastfeed

Renal Impairment 

• eGFR ≥50-79ml/min/1.73 m²: No dose adjustment recommended
• eGFR <50ml/min/1.73 m²: Caution; dose adjustment recommended
  Use only for acute schizophrenia psychosis

eGFR (ml/min/1.73m2)	Dose
≥50-79	No adjustment necessary
30-49	Initial: 12.5mg; Up-titrate by 12.5-25mg at intervals of 2-3 days, Max: 50-100mg/24hrs
≤29	Initial: 12.5mg;  Reduce the cumulative recommended daily dose by 50%

Hepatic Impairment 

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; dose adjustment recommended

Hepatic impairment	Dose
Mild (Child-Pugh class A)	No adjustment necessary
Moderate (Child-Pugh class B)	Initial: 12.5mg; Titrate by 12.5-25mg at intervals of 2-3 days; Max: 300mg/24hrs
Severe (Child-Pugh class C)	Initial: 12.5mg; Max: 100mg/24hrs

Elderly 

• No renal or hepatic co-morbidities: No dose adjustment needed
• ≥75 years with/without renal impairment: Caution; no dose adjustment recommended
  Initiate at the lower end of dosage range; Max: 50mg/24hrs

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Sedation
• Dizziness
• Seizures
• Myoclonic jerks
• Extrapyramidal symptoms 
• Headache
• Neuroleptic malignant syndrome
• Delirium
• Obsessive compulsive symptoms
• Cholinergic syndrome
• EEG changes
• Pleurothotonus
• Dysarthria
• Dysphemia
• Agitation
• Fatigue
• Neonatal drug withdrawal syndrome 

Cardiovascular Disorders

• Tachycardia
• ECG changes
• Circulatory collapse
• Arrhythmias
• Myocarditis
• Pericarditis
• Pericardial effusion
• Cardiomyopathy
• Cardiac arrest
• Myocardial infarction
• Angina pectoris
• Syncope
• Postural hypotension
• Hypertenstion
• Thromboembolism

Respiratory Disorders

• Aspiration of ingested food
• Lower respiratory tract infection 
• Respiratory depression
• Respiratory arrest 
• Nasal congestion

Gastrointestinal Disorders

• Constipation
• Hypersalivation
• Nausea and vomiting
• Anorexia
• Dry mouth
• Dysphagia
• Intestinal obstruction
• Paralytic ileus
• Faecal impaction
• Parotid gland enlargement
• Diarrhoea
• Abdominal discomfort
• Heartburn
• Dyspepsia
• Colitis

Hepatobiliary Disorders

• Increased hepatic enzymes
• Pancreatitis
• Hepatitis
• Cholestatic jaundice
• Fulminant hepatic necrosis
• Hepatic steatosis
• Hepatic necrosis
• Hepatic fibrosis
• Hepatic cirrhosis
• Hepatic injury 
• Hepatic failure

Genitourinary Disorders

• Urinary retention
• Urinary incontinence
• Interstitial nephritis
• Renal failure
• Nocturnal enuresis
• Priapism
• Retrograde ejaculation

Endocrine and Metabolic Disorders

• Pseudophaeochromocytoma
• Weight gain
• Diabetes mellitus
• Impaired glucose tolerance
• Hyperosmolar coma
• Ketoacidosis
• Severe hyperglycaemia
• Dyslipidaemia
• Benign hyperthermia
• Disturbances in sweating and temperature regulation

Musculoskeletal Disorders

• Muscle weakness
• Muscle spasms
• Muscle pain

Skin and Subcutaneous Tissue Disorders

• Skin reactions
• Pigmentation disorders

Immune, Blood and Lymphatic System Disorders

• Leukopenia 
• Neutropenia
• Eosinophilia
• Leukocytosis
• Agranulocytosis
• Anaemia
• Thrombocytopenia
• Thrombocythaemia
• Angioedema
• Leukocytoclastic vasculitis
• Systemic lupus erthematosus
• Fever

Sensory Disorders

• Blurred vision

• Bone marrow suppressants
• Depot antipsychotics
• Sulphonamides
• Pyrazolone analgesics
• Penicillamine
• Cytotoxic agents  
• Benzodiazepines
• Anticholinergics
• Alpha antagonists
• Antihypertensives
• Alcohol
• Monoamine oxidase inhibitors
• Central nervous system depressants
• Highly protein bound substances
• Warfarin
• Digoxin
• Phenytoin
• Lithium
• Sodium valproate
• QT prolonging agents 
• Agents that cause electrolyte imbalances
• CYP1A2 inducers
• CYP1A2 inhibitors

• Full blood count 
• Blood pressure 

Specific cases may require

• Hepatic function
• ECG
• Blood glucose
• Lipid profile
• Electrolytes
• Ophthalmic examination

Clozapine has weak dopamine receptor blocking activity at D1, D2, D3 and D5 receptors. It has a higher affinity for the D4 receptor. It does not induce catalepsy or inhibit apomorphine- or amphetamine-induced stereotyped behaviour. It has potent anti-alpha adrenergic, anticholinergic, antihistaminic, and arousal-reaction inhibiting effects. It has also been shown to possess antiserotoninergic properties.

Tablet 25mg 

• Aspen Clozapine (Pharmacare)
• Cloment (Litha Pharma)
• Clozapine 25 Oethmaan (Oethmaan Biosims)
• Leponex 25mg (Mylan) originator

Tablet 50mg

• Clozapine Oethmaan (Oethmaan Biosims)

Tablet 100mg 

• Aspen Clozapine (Pharmacare)
• Cloment (Litha Pharma)
• Clozapine-Hexal (Sandoz)
• Clozapine 100 Oethmaan (Oethmaan Biosims)
• Leponex 100mg (Mylan) originator