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| [[Category: Drugs]][[Category: Antipsychotics, typical; Antipsychotic 2nd Generation]] | | [[Category: Drugs]][[Category: Atypical antipsychotic ]] |
| '''Clozapine''' (中文:[[氯氮平]])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:
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| *Have tried at least 2 other antipsychotic medications that did not work
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| *Are unable to tolerae other antipsychotics because of their side-effects
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| It may also be used to treat psychoses secondary to Parkinson’s disease.
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| ==Pronunciation==
| | [[:Category: Antipsychotic Drug | '''Antipsychotic Drug''']] |
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| ==Drug Names==
| | '''Drug class: [[:Category: Atypical antipsychotic | Atypical Antipsychotic]] |
| {| class="wikitable"
| | |
| !Generic Name 藥名
| | '''Clozapine (CLOZARIL)'''（中文：[[氯氮平]]） |
| !HA Code 藥物代碼
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| !Classification藥物分類
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| |- | |
| |Clozapine Tab 25 mg
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| |CLOZ01
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| |P1S1S3
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| |-
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| |Clozapine Tab 100 mg
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| |CLOZ02
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| |P1S1S3
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| |}
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|
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| ==Mechanism of Action== | | ==Common Strengths of Clozapine Tablet== |
| Clozapine has only weak dopamine-receptor-blocking activity at D1, D2, D3 and D5 receptors, but shows high potency for the D4 receptor. | | Clozapine are available in the following strengths: |
| It is also an antagonist at the serotonin 5-HT2A receptors, improving depression, anxiety and the negative cognitive symptoms associated with schizophrenia.
| | *25 mg and 100 mg tablets |
|
| |
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| ==Dosage== | | ==Drug Trade Names of Clozapine Tablet== |
| {| class="wikitable"
| | Clozaril |
| !style="text-align: left"| Indication
| |
| !style="text-align: left"| Dose
| |
| |-
| |
| !style="text-align: left"| Schizophrenia
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| |By ''mouth
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| ADULT:
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| ADULT (18 – 59 YEARS):
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| *12.5 mg 1- 2 times daily on day 1,
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| *25 – 50 mg on day 2
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| *Then increased by 25 – 50 mg daily over 14 – 21 days up to 300 mg daily in divided doses
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| *Usual dose 200 – 450 mg daily
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| *Maximum 900 mg daily
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| ADULT (≧ 60 years)
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| *12.5 ng daily on day 1
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| *25 – 37.5 mg on day 2,
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| *Then increased by 25 mg daily over 14 – 21 days up to 300 mg daily in divided doses,
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| *Usual dose 200 – 450 mg daily
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| *Maximum 900 mg daily
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| |-
| |
| !style="text-align: left"| Psychosis in Parkinson’s disease
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| |By ''mouth
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| ADULT:
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| *12.5 mg at bedtime
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| *Increased by 12.5 mg up to twice weekly
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| *Usual dose range 25 – 37.5 mg at bedtime
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| *Maximum 100 mg daily in 1 – 2 divided doses
| |
| |}
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|
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| DOSE ADJUSTMENTS DUE TO INTERACTIONS
| | ==Drug Usage== |
| Dose adjustment may be necessary if smoking started or stopped during treatment.
| | Clozapine is used for: |
| | *Treatment-resistant schizophrenia. |
| | *Reducing risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder. |
|
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|
| How long will it take before clozapine begins to work?
| | ==Mechanism of Action== |
| Some people feel the benefit of clozapine within a few days, others may need a few months or even a year.
| | Partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and antagonist at serotonin 5-HT2A receptors. |
| *1 in 3 people with TRS have an improvement within 6 weeks
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| *2 in 3 people with TRS have an improvement after one year of treatment.
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|
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| ==Side Effects== | | ==Route of ADministration== |
| 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.
| | Oral |
| It is recommended that the white blood cell count be regularly monitored.
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|
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| All side-effects are listed by system organ and frequency:
| | ==Dosages== |
| *Very common (≥ 1/10) | | *Initial dose: 12.5 mg once or twice daily |
| *Common ( ≥ 1/100 to < 1/10) | | *Target dose: 300 - 450 mg/day in divided doses |
| *Uncommon (≥ 1/1000 to < 1/100) | | *Maximum dose: 900 mg/day |
| *Rare (≥ 1/10,000 to < 1/1000)
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| *Very rare (<1/10,000)
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|
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|
| {| class = "wikitable" | | ==Side Effects== |
| !style="text-align: left"| Blood and lymphatic system disorders | | {| class="wikitable" |
| |
| | !style="text-align: left"| Frequency |
| Common: neutropenia
| | !Adverse reactions |
| Uncommon: agranulocytosis
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| Rare: anaemia
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| Very rare: thrombocytopenia
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| |- | | |- |
| !style="text-align: left"| Metabolism and nutrition disorders
| | | rowspan="5" | '''Common |
| | | | | Drowsiness and sedation: Many patients experience significant drowsiness or sedation, which can impact daily activities |
| Common: weight gain
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| Rare: diabetes mellitus
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| |- | | |- |
| !style="text-align: left"| Psychiatric disorders
| | | Weight gain: Clozapine can lead to substantial weight gain, which may increase the risk of metabolic syndrome |
| |Common: dysarthria | |
| |- | | |- |
| !style="text-align: left"| Nervous system disorders
| | | Increased salivation |
| |
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| Very common:
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| *Drowsiness/sedation
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| *Dizziness
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| Common:
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| *Seizures
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| *Extrapyramidal symptoms
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| *Akathisia
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| *Tremor
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| *Rigidity
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| *headache
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| Uncommon:
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| *neuroleptic malignant syndrome
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| Rare:
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| *confusion
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| *delirium
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| |- | | |- |
| !style="text-align: left"| Eye disorders
| | | Constipation |
| |Common: blurred vision
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| |- | | |- |
| !style="text-align: left"| Cardiac disorders
| | | Dizziness and lightheadedness: Espeically when standing up quickly, due to orthostatic hypotension |
| | | |
| Very common: tachycardia
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| Common: ECG changes
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| Rare:
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| *arrhythmias
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| *myocarditis
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| *pericarditis
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| |- | | |- |
| !style="text-align: left"| Vascular disorders
| | | rowspan="7" | '''Uncommon |
| | | | | Agranlocytosis: Clozapine can cause a significant decrease in white blood cells, leading to a higher risk of infections. Regular blood monitoring is required |
| Common:
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| *syncope
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| *postural hypotension
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| *hypertension
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| |- | | |- |
| !style="text-align: left"| Gastrointestinal disorders
| | | Seizures: The risk of seizures increase with higher doses of clozapine |
| |
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| Very common:
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| *constipation
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| *hypersalivation
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| Common:
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| *nausea
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| *vomiting
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| *anorexia
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| *dry mouth
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| |- | | |- |
| !style="text-align: left"| Hepatobiliary disorders
| | | Myocarditis and cardiomyopathy |
| |
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| Common: elevated liver enzymes
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| Rare:
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| *pancreatitis
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| *hepatitis
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| *cholestatic jaundice
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| |- | | |- |
| !style="text-align: left"| Renal and urinary disorders
| | | Neuroleptic Malignant Syndrome (NMS): This is a rare but potentially fatal condition characterized by high fever, muscle stiffness, and altered mental status |
| |Common: urinary retention | |
| |}
| |
| | |
| ==Pharmacokinetics==
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| {|class="wikitable"
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| !style="text-align: left"| Oral bioavailability
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| |The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism.
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| |- | | |- |
| !style="text-align: left"| Onset of action
| | | Tardive dyskinesia: This is a movement disorder that may become irreversible with prolonged use, particularly in older adults |
| |Peak plasma concentration is achieved about 2.5 hours after an oral dose.
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| |- | | |- |
| !style="text-align: left"| Metabolism
| | | QT prolongation |
| |It is metabolized in the liver, via enzymes CYP1A2, CYP2D6 and CYP3A4.
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| |- | | |- |
| !style="text-align: left"| Elimination half-life
| | | Liver issues: Symptoms may include jaundice, dark urine, and abdominal pain |
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| It is eliminated via urine and faeces.
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| | |
| The elimination half-life is approximately 14 hours at steady state conditions.
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| |} | | |} |
|
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| ==Drug Management== | | ==Pharmacokinetics== |
| ===Monitoring===
| | *Pharmacologic effects (e.g. sedation) are apparent within 15 minutes |
| *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. | | *Peak plasma concentrations are typically attained within 1.5 to 2.5 hours after single or multiple doses of clozapine tablets |
| *Close medical supervision during initiation (risk of collapse because of hypotension and convulsions). | | *Elimination half-life: 8 hours (single dose), 12 hours (multiples doses) |
| *Blood lipids and weight should be measured at baseline, and then at regular intervals.
| | *Approximately 50% excreted in urine, 30% in feces |
| *Fasting blood glucose should be measured at baseline, at 4-6 months, and then yearly. | |
| '''Treatment Cessation'''
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|
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| On planned withdrawal reduce dose over 1 – 2 weeks to avoid risk of rebound psychosis. If abrupt withdrawal necessary observe patient carefully.
| | ==Drug Precautions== |
| | '''Pregnancy |
|
| |
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| ===Drug interaction===
| | Use caution; potential risks to the fetus should be considered |
| 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.
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| {| class="wikitable"
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| !style="text-align: left"| Drugs given with clozapine
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| !style="text-align: left"| Potential Effect
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| |-
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| |style="text-align: left"|
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| *CNS-depressant drugs including alcohol, hypnotics, anxiolytics, sedative H1 antihistamines, central antihypertensives, baclofen, thalidomide and opioids.
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| |
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| Potentiates the sedative effect.
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| |-
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| |style="text-align: left"|
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| *Lithium
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| |Increased risk of extrapyramidal side-effects and possibly neurotoxicity
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| |-
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| |style="text-align: left"|
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| *Metoclopramide
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| |Increased risk of extrapyramidal side-effects
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| |-
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| |style="text-align: left"|
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| *Strong CYP2D6 inhibitors such as quinidine, fluoxetine and paroxetine.
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| |May result in higher plasma concentrations of clozapine, increased risk of toxicity.
| |
| |-
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| |style="text-align: left"|
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| *Strong CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors
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| |May result in higher plasma concentrations of clozapine, increased risk of toxicity.
| |
| |-
| |
| |style="text-align: left"|
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| *Strong CYP3A4 inducers, such as carbamazepine, rifampicin, phenytoin, phenobarbitone and St John’s Wort.
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| |May lower plasma concentrations of aripiprazole, so should increase clozapine dose.
| |
| |-
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| |style="text-align: left"|
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| *Drugs that prolong the QT interval e.g. amiodarone, sotalol, quinidine, flecainide
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| *Drugs which induce bradycardia e.g. diltiazem, verapamil
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| *Drugs which can cause hypokalaemia such as diuretics e.g. frusemide
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| |An increased risk of ventricular arrhythmias – avoid concomitant use.
| |
| |}
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|
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| ===Caution===
| | '''Breastfeeding |
| *age over 60 years
| |
| *prostatic hypertrophy
| |
| *susceptibility to angle-closure glaucoma
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| *taper off other antipsychotics before starting
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|
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|
| ===Contra-indications===
| | Contraindicated during lactation |
| *Severe cardiac disorders (e.g. myocarditis;
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| *History of neutropenia or agranulocytosis;
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| *Bone-marrow disorders
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| *Paralytic ileus;
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| *Alcoholic and toxic psychoses
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| *History of circulatory collapse
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| *Drug intoxication
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| *Coma or severe CNS depression
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| *Uncontrolled epilepsy
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|
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|
| ===Hepatic impairment===
| | '''Children & Elderly |
| *Avoid in symptomatic liver disease | | *Contraindicated in children before puberty |
| *Avoid in progressive liver disease | | *Use caution in elderly patients |
| *Avoid in hepatic failure
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| *Monitor hepatic function regularly
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|
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|
| ===Renal impairment===
| | '''Monitoring Requirements |
| avoid in severe impairment
| |
|
| |
|
| ===Pregnancy===
| | Patients on clozapine require regular monitoring, including: |
| use with caution
| | *Frequent blood test to monitor white blood cell counts. |
| | *Cardiac monitoring to detect any changes in heart rhythm. |
| | *Regular metabolic assessments to check for weight gain, blood sugar levels, and lipid profiles. |
|
| |
|
| ===Breast-feeding===
| | '''Drug Interactions |
| Use during breast feeding should be avoided.
| |
|
| |
|
| ===Driving and skilled tasks===
| | Interactions with strong CYP1A2 inhibitors, CYP2D6 inhibitors, and CYP3A4 inducers |
| 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.
| | *CYP1A2 Inhibitors |
| | **Drugs such as fluvoxamine, ciprofloxacin, and hormonal contraceptives can increase clozapine levels, raising the risk of adverse effects |
| | *CYP1A2 inducers |
| | **Substances like omeprazole can decrease clozapine levels, potentially reducing its efficacy |
| | *Lamotrigine |
| | **THis anticonvulsant can increase clozapine levels, requiring close monitoring |
| | *Caffeine |
| | **Can increase clozapine levels due to CYP1A2 inhibition |
| | *Grapefruit Juice |
| | **May increase clozapine levels bhy inhibiting CYP3A4 |
| | *Smoking |
| | **Can decrease clozapine levels; cessation can lead to increase plasma levles and potential toxicity |
|
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|
| ==FAQ== | | ==FAQ== |
| ===How should I take the tablet?===
| | '''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?===
| | Take with or without food. |
| You may experience some, or all, of the following:
| | |
| *You feel better, becoming less withdrawn and more involved in life around you
| | '''What should I avoid while taking? |
| *Your ability to concentrate improves
| | |
| *Your relationships improve and you find it easier to mix with people
| | Avoid activities requiring mental alertness until you know how the medication affects you. |
| *You may feel less aggressive and more able to control your anger
| | |
| === What should I avoid while taking?===
| | '''What Happens if I Miss a Dose? |
| 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.
| | Take the missed dose as soon as you remember unless it is almost time for your next dose. Do not double doses. |
| ===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. | |
Antipsychotic Drug
Drug class: Atypical Antipsychotic
Clozapine (CLOZARIL)（中文：氯氮平）
Common Strengths of Clozapine Tablet[edit]
Clozapine are available in the following strengths:
Drug Trade Names of Clozapine Tablet[edit]
Clozaril
Drug Usage[edit]
Clozapine is used for:
- Treatment-resistant schizophrenia.
- Reducing risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorder.
Mechanism of Action[edit]
Partial agonist at dopamine D2 and serotonin 5-HT1A receptors, and antagonist at serotonin 5-HT2A receptors.
Route of ADministration[edit]
Oral
Dosages[edit]
- Initial dose: 12.5 mg once or twice daily
- Target dose: 300 - 450 mg/day in divided doses
- Maximum dose: 900 mg/day
Side Effects[edit]
| Frequency
|
Adverse reactions
|
| Common
|
Drowsiness and sedation: Many patients experience significant drowsiness or sedation, which can impact daily activities
|
| Weight gain: Clozapine can lead to substantial weight gain, which may increase the risk of metabolic syndrome
|
| Increased salivation
|
| Constipation
|
| Dizziness and lightheadedness: Espeically when standing up quickly, due to orthostatic hypotension
|
| Uncommon
|
Agranlocytosis: Clozapine can cause a significant decrease in white blood cells, leading to a higher risk of infections. Regular blood monitoring is required
|
| Seizures: The risk of seizures increase with higher doses of clozapine
|
| Myocarditis and cardiomyopathy
|
| Neuroleptic Malignant Syndrome (NMS): This is a rare but potentially fatal condition characterized by high fever, muscle stiffness, and altered mental status
|
| Tardive dyskinesia: This is a movement disorder that may become irreversible with prolonged use, particularly in older adults
|
| QT prolongation
|
| Liver issues: Symptoms may include jaundice, dark urine, and abdominal pain
|
Pharmacokinetics[edit]
- Pharmacologic effects (e.g. sedation) are apparent within 15 minutes
- Peak plasma concentrations are typically attained within 1.5 to 2.5 hours after single or multiple doses of clozapine tablets
- Elimination half-life: 8 hours (single dose), 12 hours (multiples doses)
- Approximately 50% excreted in urine, 30% in feces
Drug Precautions[edit]
Pregnancy
Use caution; potential risks to the fetus should be considered
Breastfeeding
Contraindicated during lactation
Children & Elderly
- Contraindicated in children before puberty
- Use caution in elderly patients
Monitoring Requirements
Patients on clozapine require regular monitoring, including:
- Frequent blood test to monitor white blood cell counts.
- Cardiac monitoring to detect any changes in heart rhythm.
- Regular metabolic assessments to check for weight gain, blood sugar levels, and lipid profiles.
Drug Interactions
Interactions with strong CYP1A2 inhibitors, CYP2D6 inhibitors, and CYP3A4 inducers
- CYP1A2 Inhibitors
- Drugs such as fluvoxamine, ciprofloxacin, and hormonal contraceptives can increase clozapine levels, raising the risk of adverse effects
- CYP1A2 inducers
- Substances like omeprazole can decrease clozapine levels, potentially reducing its efficacy
- Lamotrigine
- THis anticonvulsant can increase clozapine levels, requiring close monitoring
- Caffeine
- Can increase clozapine levels due to CYP1A2 inhibition
- Grapefruit Juice
- May increase clozapine levels bhy inhibiting CYP3A4
- Smoking
- Can decrease clozapine levels; cessation can lead to increase plasma levles and potential toxicity
How Should I Take the Tablet?
Take with or without food.
What should I avoid while taking?
Avoid activities requiring mental alertness until you know how the medication affects you.
What Happens if I Miss a Dose?
Take the missed dose as soon as you remember unless it is almost time for your next dose. Do not double doses.
