Clozapine

1. Drug Name

• Generic Name: Clozapine

• Brand Names: Clozaril, FazaClo, Versacloz, Denzapine, among others.

2. Drug Classification

• Class: Atypical Antipsychotic

• Subclass: Second-Generation Antipsychotic (SGA)

3. Mechanism of Action

• Clozapine is an atypical antipsychotic that works through a complex interaction with several neurotransmitter systems.

• Dopamine D2 Receptor Antagonism: It has a low affinity for dopamine D2 receptors compared to other antipsychotics, which is thought to contribute to its lower risk of extrapyramidal symptoms (EPS).

• Serotonin (5-HT2A) Receptor Antagonism: Clozapine also acts as an antagonist at serotonin 5-HT2A receptors, which is thought to enhance its antipsychotic efficacy and reduce the risk of tardive dyskinesia.

• Additional Receptor Interactions:

  • Alpha-1 adrenergic: Clozapine has a high affinity for alpha-1 receptors, which may contribute to its sedative and hypotensive effects.

  • Muscarinic cholinergic receptors: It also has anticholinergic activity, which may contribute to side effects such as dry mouth, constipation, and blurred vision.

  • Histamine (H1): Its antagonism at H1 receptors contributes to sedative effects but may also cause weight gain and drowsiness.

4. Pharmacokinetics

• Absorption: Clozapine is well absorbed after oral administration, with an oral bioavailability of approximately 50-60%, which is reduced due to first-pass metabolism in the liver.

• Distribution:

  • Volume of distribution (Vd): Approximately 1000-1500 L, indicating extensive tissue distribution, including into the brain.

  • Protein binding: Clozapine is highly protein-bound (~95%).

• Metabolism: Clozapine is primarily metabolized in the liver by CYP1A2, CYP3A4, and CYP2D6 enzymes. It is metabolized into several active metabolites, including N-desmethylclozapine, which has antipsychotic activity.

• Excretion:

  • Half-life (t½): The half-life of clozapine is approximately 12 hours, but its active metabolite, N-desmethylclozapine, has a longer half-life.

  • Excretion: The majority of clozapine and its metabolites are excreted in the urine (approximately 50-60%) and feces (approximately 30-40%).

• Special Considerations:

  • Clozapine clearance can be affected by liver disease and smoking (inducing CYP1A2). Dose adjustments may be necessary.

5. Indications

• Primary Indications:

  • Treatment-resistant schizophrenia: Clozapine is FDA-approved for patients with schizophrenia who have not responded to at least two other antipsychotic treatments.

  • Reduction of suicidal behavior in schizophrenia and schizoaffective disorder: It is effective in reducing the risk of suicide in patients with schizophrenia or schizoaffective disorder.

• Off-label Uses:

  • Bipolar Disorder: Clozapine is occasionally used for patients with bipolar disorder, particularly those who have failed other treatments.

  • Agitation and aggression: In certain settings like neurodegenerative diseases or severe agitation, clozapine may be used.

  • Parkinson's disease psychosis: Though not FDA-approved for this indication, it is sometimes used off-label in the treatment of psychotic symptoms in Parkinson's disease.

• Special Populations:

  • Effective in treatment-resistant schizophrenia, where patients have tried multiple medications without success.

6. Dosage and Administration

• Adult Dosing:

  • Schizophrenia: Start with 12.5 mg once or twice a day, then gradually increase by 25-50 mg/day every 1-2 days. Usual maintenance dose: 300-450 mg/day, with a maximum dose of 900 mg/day.

  • Suicide Risk Reduction: Same dosage as schizophrenia.

• Pediatric Dosing:

  • Generally not recommended for children under 16 years unless specifically prescribed under close monitoring.

• Route of Administration: Oral tablet, orally disintegrating tablet, or suspension.

• Dosing Adjustments:

  • For patients with hepatic impairment, dose reduction is necessary.

  • Renal impairment: No significant dose adjustment required, but caution is advised.

  • Clozapine clearance is reduced in smokers, and dose adjustments may be required based on smoking status.

7. Contraindications

• Absolute Contraindications:

  • Known hypersensitivity to clozapine or any of its components.

  • Severe granulocytopenia (absolute neutrophil count <1000/μL) or agranulocytosis.

  • Paralytic ileus (intestinal obstruction).

• Relative Contraindications:

  • Use with caution in patients with cardiovascular disease (e.g., history of myocardial infarction or arrhythmias) due to the risk of hypotension, QT prolongation, and cardiac arrest.

  • Caution in patients with seizure disorders, as clozapine lowers the seizure threshold.

8. Warnings and Precautions

• Black Box Warning:

  • Agranulocytosis: Clozapine carries a black box warning due to the risk of severe neutropenia (low white blood cell count) and agranulocytosis, which requires regular blood monitoring (weekly for the first six months, then every 2 weeks thereafter).

  • Seizures: Clozapine lowers the seizure threshold, increasing the risk of seizures, particularly at higher doses.

  • Myocarditis and Cardiomyopathy: These conditions are associated with clozapine and require careful monitoring.

• Other Warnings:

  • Orthostatic Hypotension: Especially at the beginning of treatment, patients may experience hypotension and syncope.

  • Metabolic Syndrome: Regular monitoring for weight gain, diabetes, and lipid abnormalities is advised.

  • QT Prolongation: Clozapine may cause QT interval prolongation and should be used cautiously in patients with existing cardiac conditions.

9. Adverse Effects

• Common Adverse Effects:

  • Sedation, dizziness, weight gain, constipation, hypotension.

• Less Common but Clinically Significant:

  • Agranulocytosis, seizures, myocarditis, pericarditis.

• Rare/Serious:

  • Neuroleptic Malignant Syndrome (NMS): Rare, but life-threatening condition with fever, rigidity, altered mental status, autonomic instability.

  • Tardive Dyskinesia: A rare but serious movement disorder.

  • Thromboembolism: Increased risk of venous thromboembolism (VTE).

10. Drug Interactions

• Major Drug Interactions:

  • CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin) increase clozapine levels.

  • CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) can also increase levels.

  • Benzodiazepines and other CNS depressants: Concurrent use may increase sedation and the risk of respiratory depression.

  • Anticholinergic drugs: Concurrent use can exacerbate anticholinergic side effects (e.g., constipation, urinary retention).

• Food-Drug Interactions:

  • Clozapine absorption is not significantly affected by food.

• Lab Test Interactions:

  • White blood cell count (WBC): Regular monitoring is required due to the risk of agranulocytosis.

  • Glucose levels: Clozapine can cause hyperglycemia and should be monitored.

11. Clinical Pharmacology

• Clozapine’s antipsychotic effects are thought to be mediated by its ability to block dopamine and serotonin receptors in brain regions involved in mood and cognition. Its unique profile allows it to effectively manage positive symptoms of schizophrenia and negative symptoms while minimizing extrapyramidal side effects.

12. Special Populations

• Pregnancy: Category C. Clozapine should only be used during pregnancy if the benefits outweigh the risks. Neonatal withdrawal symptoms and sedation may occur.

• Lactation: Clozapine is excreted in breast milk, and the infant should be monitored for adverse effects, including sedation and weight gain.

• Geriatrics: Older adults may be more susceptible to clozapine’s sedative and hypotensive effects. Start with lower doses and increase gradually.

• Renal or Hepatic Dysfunction: Dose adjustments may be required for patients with liver disease due to reduced metabolism.

13. Therapeutic Uses

• First-Line: Not typically used as a first-line treatment due to its side effect profile but is reserved for treatment-resistant schizophrenia.

• Second-Line: Used when other antipsychotics have failed or caused intolerable side effects.

• Clinical Trials: Studies show that clozapine is significantly more effective than other antipsychotics in treatment-resistant schizophrenia.

14. Monitoring and Follow-Up

• Before Treatment: Baseline white blood cell count (WBC), ECG, weight, lipid profile, blood glucose.

• During Treatment: Regular monitoring of WBC, liver function, lipid profile, blood glucose, and weight.

• Therapeutic Levels: No therapeutic drug level monitoring is required, but clinical efficacy should guide dosing.

15. Overdose Management

• Symptoms of Overdose: Severe sedation, hypotension, seizures, respiratory depression.

• Treatment Protocol:

  • Activated charcoal if within 1 hour of ingestion.

  • Symptomatic and supportive treatment, including IV fluids, respiratory support, and cardiovascular monitoring.

• Antidote: No specific antidote.

16. Patient Counseling Information

• Key Points:

  • Take clozapine exactly as prescribed, usually once or twice daily.

  • Regular blood tests are required to monitor for potential agranulocytosis.

  • Report any unusual signs of infection, sore throat, fever, or easy bruising.

• Signs for Immediate Medical Attention:

  • Symptoms of severe sedation, fainting, heart palpitations, or difficulty breathing.

  • Unexplained fever, sore throat, or mouth ulcers.