Clozapine

Clozapine (中文:[[ ]])is an atypical antipsychotic or 2nd Generation antipsychotic medication. It is specifically used to treat treatment resistant schizophrenia (TRS), which affects approximately 1 in 3 people with the condition. These people include those who:

• Have tried at least 2 other antipsychotic medications that did not work
• Are unable to tolerae other antipsychotics because of their side-effects

It may also be used to treat psychoses secondary to Parkinson’s disease.

Drug Names

Generic Name 藥名	HA Code 藥物代碼	Classification藥物分類
Clozapine Tab 25 mg	CLOZ01	P1S1S3
Clozapine Tab 100 mg	CLOZ02	P1S1S3

Mechanism of Action

Clozapine has only weak dopamine-receptor-blocking activity at D1, D2, D3 and D5 receptors, but shows high potency for the D4 receptor. It is also an antagonist at the serotonin 5-HT2A receptors, improving depression, anxiety and the negative cognitive symptoms associated with schizophrenia.

Dosage

Indication	Dose
Schizophrenia	By mouth ADULT: ADULT (18 – 59 YEARS): 12.5 mg 1- 2 times daily on day 1, 25 – 50 mg on day 2 Then increased by 25 – 50 mg daily over 14 – 21 days up to 300 mg daily in divided doses Usual dose 200 – 450 mg daily Maximum 900 mg daily ADULT (≧ 60 years) 12.5 ng daily on day 1 25 – 37.5 mg on day 2, Then increased by 25 mg daily over 14 – 21 days up to 300 mg daily in divided doses, Usual dose 200 – 450 mg daily Maximum 900 mg daily
Psychosis in Parkinson’s disease	By mouth ADULT: 12.5 mg at bedtime Increased by 12.5 mg up to twice weekly Usual dose range 25 – 37.5 mg at bedtime Maximum 100 mg daily in 1 – 2 divided doses

DOSE ADJUSTMENTS DUE TO INTERACTIONS Dose adjustment may be necessary if smoking started or stopped during treatment.

How long will it take before clozapine begins to work? Some people feel the benefit of clozapine within a few days, others may need a few months or even a year.

• 1 in 3 people with TRS have an improvement within 6 weeks
• 2 in 3 people with TRS have an improvement after one year of treatment.

Side Effects

Clozapine is associated with a relatively high risk of low white blood cells. It specifically affects a type of white blood cell called neutrophil. Neutrophils help the body to fight infections. A small fall in neutrophil levels leads to a condition called neutropenia, while a big fall is called agranulocytosis. Agranulocytosis and neutropenia are uncommon. However, if they occur, it is usually within the first 18 weeks of clozapine treatment. It is recommended that the white blood cell count be regularly monitored.

All side-effects are listed by system organ and frequency:

• Very common (≥ 1/10)
• Common ( ≥ 1/100 to < 1/10)
• Uncommon (≥ 1/1000 to < 1/100)
• Rare (≥ 1/10,000 to < 1/1000)
• Very rare (<1/10,000)

Blood and lymphatic system disorders	Common: neutropenia Uncommon: agranulocytosis Rare: anaemia Very rare: thrombocytopenia
Metabolism and nutrition disorders	Common: weight gain Rare: diabetes mellitus
Psychiatric disorders	Common: dysarthria
Nervous system disorders	Very common: Drowsiness/sedation Dizziness Common: Seizures Extrapyramidal symptoms Akathisia Tremor Rigidity headache Uncommon: neuroleptic malignant syndrome Rare: confusion delirium
Eye disorders	Common: blurred vision
Cardiac disorders	Very common: tachycardia Common: ECG changes Rare: arrhythmias myocarditis pericarditis
Vascular disorders	Common: syncope postural hypotension hypertension
Gastrointestinal disorders	Very common: constipation hypersalivation Common: nausea vomiting anorexia dry mouth
Hepatobiliary disorders	Common: elevated liver enzymes Rare: pancreatitis hepatitis cholestatic jaundice
Renal and urinary disorders	Common: urinary retention

Pharmacokinetics

Oral bioavailability	The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism.
Onset of action	Peak plasma concentration is achieved about 2.5 hours after an oral dose.
Metabolism	It is metabolized in the liver, via enzymes CYP1A2, CYP2D6 and CYP3A4.
Elimination half-life	It is eliminated via urine and faeces. The elimination half-life is approximately 14 hours at steady state conditions.

Drug Management

Monitoring

• clozapine requires white blood cell monitoring weekly for 18 weeks, then fortnightly for up to 1 year, and then monthly as part of the clozapine patient monitoring.
• Close medical supervision during initiation (risk of collapse because of hypotension and convulsions).
• Blood lipids and weight should be measured at baseline, and then at regular intervals.
• Fasting blood glucose should be measured at baseline, at 4-6 months, and then yearly.

Treatment Cessation

On planned withdrawal reduce dose over 1 – 2 weeks to avoid risk of rebound psychosis. If abrupt withdrawal necessary observe patient carefully.

Drug interaction

Avoid concomitant use of clozapine with drugs that have a substantial potential for causing agranulocytosis. Aripiprazole is metabolized by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

Drugs given with clozapine	Potential Effect
CNS-depressant drugs including alcohol, hypnotics, anxiolytics, sedative H1 antihistamines, central antihypertensives, baclofen, thalidomide and opioids.	Potentiates the sedative effect.
Lithium	Increased risk of extrapyramidal side-effects and possibly neurotoxicity
Metoclopramide	Increased risk of extrapyramidal side-effects
Strong CYP2D6 inhibitors such as quinidine, fluoxetine and paroxetine.	May result in higher plasma concentrations of clozapine, increased risk of toxicity.
Strong CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors	May result in higher plasma concentrations of clozapine, increased risk of toxicity.
Strong CYP3A4 inducers, such as carbamazepine, rifampicin, phenytoin, phenobarbitone and St John’s Wort.	May lower plasma concentrations of aripiprazole, so should increase clozapine dose.
Drugs that prolong the QT interval e.g. amiodarone, sotalol, quinidine, flecainide Drugs which induce bradycardia e.g. diltiazem, verapamil Drugs which can cause hypokalaemia such as diuretics e.g. frusemide	An increased risk of ventricular arrhythmias – avoid concomitant use.

Caution

• age over 60 years
• prostatic hypertrophy
• susceptibility to angle-closure glaucoma
• taper off other antipsychotics before starting

Contra-indications

• Severe cardiac disorders (e.g. myocarditis;
• History of neutropenia or agranulocytosis;
• Bone-marrow disorders
• Paralytic ileus;
• Alcoholic and toxic psychoses
• History of circulatory collapse
• Drug intoxication
• Coma or severe CNS depression
• Uncontrolled epilepsy

Hepatic impairment

• Avoid in symptomatic liver disease
• Avoid in progressive liver disease
• Avoid in hepatic failure
• Monitor hepatic function regularly

Renal impairment

avoid in severe impairment

Pregnancy

use with caution

Breast-feeding

Use during breast feeding should be avoided.

Driving and skilled tasks

Drivers and machine operators should be told about the risk of drowsiness with this medication especially at the start of treatment. Affected patients should not drive or operate machinery.

FAQ

How should I take the tablet?

You will be prescribed the lowest dose needed to control your symptoms. The tablet should be swallowed whole with a glass of water. It is important to keep taking the tablet even if your symptoms improve or completely disappear. If you stop taking clozapine, your symptoms could come back.

How will I know that clozapine is working?

You may experience some, or all, of the following:

• You feel better, becoming less withdrawn and more involved in life around you
• Your ability to concentrate improves
• Your relationships improve and you find it easier to mix with people
• You may feel less aggressive and more able to control your anger

What should I avoid while taking?

Avoid drinking alcohol while taking clozapine because it may enhance the side effects of sedation. Changing your smoking habits and the amount of caffeine you drink (in things such as tea, coffee or cola) can affect the amount of clozapine in your blood. Mention any such changes to your doctor.

What happen if I overdose?

Contact your primary care doctor. If emergency situation, call 999

What happen if I miss a dose?

Take it as soon as you remember. If it is near the time of the next dose, skip the missed dose. Take your next dose at the regular time. Do not double the dose to catch up.