Clozapine: Difference between revisions

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[[Category: Drugs]][[Category: Antipsychotics, typical; Antipsychotic 2nd Generation]]
[[Category: Drugs]][[Category: Atypical antipsychotic ]]
'''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.


==Pronunciation==
[[:Category: Antipsychotic Drug | '''Antipsychotic Drug''']]


==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
!Classification藥物分類
|-
|Clozapine Tab 25 mg
|CLOZ01
|P1S1S3
|-
|Clozapine Tab 100 mg
|CLOZ02
|P1S1S3
|}


==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


==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 
|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
|-
!style="text-align: left"| 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
==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.


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
*2 in 3 people with TRS have an improvement after one year of treatment.


==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.


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)
*Very rare (<1/10,000)


{| 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
|-
Rare: anaemia
| rowspan="5" | '''Common
Very rare: thrombocytopenia
| 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
|-
|-
!style="text-align: left"| Metabolism and nutrition disorders
| Constipation
|
Common: weight gain
Rare: diabetes mellitus
|-
|-
!style="text-align: left"| Psychiatric disorders
| Dizziness and lightheadedness: Espeically when standing up quickly, due to orthostatic hypotension
|Common: dysarthria
|-
|-
!style="text-align: left"| Nervous system 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
Very common:
*Drowsiness/sedation
*Dizziness
Common:
*Seizures
*Extrapyramidal symptoms
*Akathisia
*Tremor
*Rigidity
*headache
Uncommon:
*neuroleptic malignant syndrome
Rare:
*confusion
*delirium
|-
|-
!style="text-align: left"| Eye disorders
| Seizures: The risk of seizures increase with higher doses of clozapine
|Common: blurred vision
|-
|-
!style="text-align: left"| Cardiac disorders
| Myocarditis and cardiomyopathy
|
Very common: tachycardia
Common: ECG changes
Rare:
*arrhythmias
*myocarditis
*pericarditis
|-
|-
!style="text-align: left"| Vascular disorders
| Neuroleptic Malignant Syndrome (NMS): This is a rare but potentially fatal condition characterized by high fever, muscle stiffness, and altered mental status
|
Common:
*syncope
*postural hypotension
*hypertension
|-
|-
!style="text-align: left"| Gastrointestinal disorders
| Tardive dyskinesia: This is a movement disorder that may become irreversible with prolonged use, particularly in older adults
|
Very common:
*constipation
*hypersalivation
Common:
*nausea
*vomiting
*anorexia
*dry mouth
|-
|-
!style="text-align: left"| Hepatobiliary disorders
| QT prolongation
|
Common: elevated liver enzymes
Rare:
*pancreatitis
*hepatitis
*cholestatic jaundice
|-
|-
!style="text-align: left"| Renal and urinary disorders
| Liver issues: Symptoms may include jaundice, dark urine, and abdominal pain
|Common: urinary retention
|}
|}


==Pharmacokinetics==
==Pharmacokinetics==
{|class="wikitable"
*Pharmacologic effects (e.g. sedation) are apparent within 15 minutes
!style="text-align: left"| Oral bioavailability
*Peak plasma concentrations are typically attained within 1.5 to 2.5 hours after single or multiple doses of clozapine tablets
|The absorption of clozapine is almost complete following oral administration, but the oral bioavailability is only 60 to 70% due to first-pass metabolism.
*Elimination half-life: 8 hours (single dose), 12 hours (multiples doses)
|-
*Approximately 50% excreted in urine, 30% in feces
!style="text-align: left"| Onset of action
 
|Peak plasma concentration is achieved about 2.5 hours after an oral dose.
==Drug Precautions==
|-
'''Pregnancy
!style="text-align: left"| Metabolism
 
|It is metabolized in the liver, via enzymes CYP1A2, CYP2D6 and CYP3A4.
Use caution; potential risks to the fetus should be considered
|-
 
!style="text-align: left"| Elimination half-life
'''Breastfeeding
|
 
It is eliminated via urine and faeces.
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
 
==FAQ==
'''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.


The elimination half-life is approximately 14 hours at steady state conditions.
'''What Happens if I Miss a Dose?
|}


==Drug Management==
Take the missed dose as soon as you remember unless it is almost time for your next dose. Do not double doses.
===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.

Latest revision as of 22:11, 21 July 2024


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:

  • 25 mg and 100 mg tablets

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

FAQ[edit]

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.

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