Clozaril: Atypical Antipsychotic for Treatment-Resistant Schizophrenia
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Synonyms | |||
Clozaril (clozapine) represents a cornerstone in the pharmacological management of treatment-resistant schizophrenia, a severe mental health condition where standard antipsychotic therapies have proven inadequate. As the first atypical antipsychotic approved by the FDA, its unique receptor profile distinguishes it from both first and second-generation alternatives, offering a critical therapeutic option for a complex patient population. Its use is strictly regulated under a Risk Evaluation and Mitigation Strategy (REMS) program due to the potential for serious adverse effects, necessitating rigorous clinical oversight and mandatory blood monitoring. This expert guide details the essential information regarding its mechanism, application, and safety protocols for healthcare professionals managing severe psychotic disorders.
Features
- Active Pharmaceutical Ingredient: Clozapine.
- Pharmacological Class: Dibenzodiazepine derivative; Atypical Antipsychotic.
- Key Mechanism: Antagonism at dopamine D4 and serotonin 5-HT2A receptors, with additional affinity for adrenergic, cholinergic, and histaminergic receptors.
- Administration: Oral tablets.
- Available Strengths: 25 mg and 100 mg tablets.
- Regulatory Status: Subject to a mandatory FDA-approved Risk Evaluation and Mitigation Strategy (REMS) program.
Benefits
- Provides effective symptom control for patients with treatment-resistant schizophrenia, where other antipsychotics have failed.
- Demonstrates superior efficacy in reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
- Associated with a lower incidence of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) compared to typical antipsychotics.
- Can lead to significant improvements in negative symptoms (e.g., apathy, social withdrawal) and cognitive function.
- Offers a vital therapeutic pathway for severely ill patients, potentially enabling functional recovery and enhanced quality of life.
Common use
Clozaril is primarily indicated for:
- The treatment of severely ill patients with treatment-resistant schizophrenia. Failure to respond to adequate trials of at least two different standard antipsychotic drugs is required for this diagnosis.
- For reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior.
Its use is reserved for these specific populations due to its significant safety profile and is not a first-line treatment option.
Dosage and direction
Initial Dose Titration: Treatment must be initiated at a low dose, typically 12.5 mg once or twice daily, and carefully titrated upward based on clinical response and tolerability. A slow titration is imperative to minimize risks of hypotension, bradycardia, and syncope.
Target Therapeutic Dose: The effective dosage range is typically 300 mg to 450 mg per day, administered in divided doses, by the end of a 2-week period. Subsequent dosage adjustments should not exceed 100 mg once or twice weekly.
Maximum Dose: Doses should not exceed 900 mg per day.
Administration: Can be taken with or without food to minimize gastrointestinal upset. Consistent daily administration is critical.
Monitoring: Absolute necessity for absolute neutrophil count (ANC) monitoring before initiation, during titration, and throughout therapy as mandated by the Clozapine REMS Program.
Precautions
- Agranulocytosis: Clozaril carries a significant risk of severe neutropenia and agranulocytosis. This risk mandates continuous hematological monitoring through the Clozapine REMS program. Treatment must not begin if the baseline ANC is less than 1500/µL.
- Seizures: Dose-dependent risk of seizures. Use with caution in patients with a history of seizures or predisposing conditions.
- Myocarditis and Cardiomyopathy: Can occur, particularly during the first month of therapy. Monitor for symptoms such as unexplained fatigue, dyspnea, tachypnea, fever, chest pain, and palpitations.
- Orthostatic Hypotension, Bradycardia, and Syncope: Risk is highest during initial titration. Caution is advised in patients with cardiovascular or cerebrovascular disease.
- Metabolic Changes: Can cause weight gain, hyperglycemia, and dyslipidemia. Baseline and periodic monitoring of weight, blood glucose, and lipid profiles is essential.
- Elderly Patients with Dementia-Related Psychosis: Clozaril is not approved for this use. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
Contraindications
- History of clozapine-induced agranulocytosis or severe granulocytopenia.
- Myeloproliferative disorders.
- Uncontrolled epilepsy.
- Severe central nervous system depression or comatose states.
- Simultaneous use with other drugs known to have a substantial potential for causing agranulocytosis (e.g., carbamazepine).
- Hypersensitivity to clozapine or any other component of the formulation.
Possible side effect
Very Common (>10%): Sedation/somnolence, dizziness, tachycardia, constipation, hypersalivation (sialorrhea), weight gain.
Common (1-10%): Orthostatic hypotension, hyperthermia, nausea, vomiting, dry mouth, blurred vision, headache, tremor, night sweats, fever.
Serious (Require Immediate Medical Attention):
- Signs of infection (e.g., fever, sore throat, weakness) indicating possible agranulocytosis.
- Symptoms of myocarditis (e.g., chest pain, shortness of breath, palpitations).
- Seizures.
- Signs of venous thromboembolism (e.g., chest pain, shortness of breath, leg pain or swelling).
- Neuroleptic Malignant Syndrome (NMS) - hyperpyrexia, muscle rigidity, altered mental status.
- Severe gastrointestinal hypomotility, which can lead to paralytic ileus and death.
Drug interaction
- Bone Marrow Suppressing Agents (e.g., chemotherapy, carbamazepine): Concomitant use is contraindicated due to additive risk of agranulocytosis.
- Benzodiazepines and other CNS Depressants (e.g., opioids, alcohol): May potentiate CNS depression, increasing risk of respiratory depression and sedation.
- Strong CYP1A2 Inhibitors (e.g., fluvoxamine, ciprofloxacin): Can significantly increase clozapine plasma levels, increasing toxicity risk. Dose reduction may be necessary.
- Strong CYP1A2 Inducers (e.g., tobacco smoking, rifampin): Can significantly decrease clozapine plasma levels, potentially reducing efficacy. Smokers who cease smoking may experience a rapid rise in clozapine levels.
- Drugs that Prolong QT Interval (e.g., certain antibiotics, antiarrhythmics): May have additive effects on cardiac repolarization, increasing risk of arrhythmias.
- Antihypertensive Agents: May potentiate hypotensive effects.
Missed dose
If a dose is missed, it should be taken as soon as it is remembered. However, if it is close to the time of the next scheduled dose, the missed dose should be skipped. Patients should never take a double dose to make up for a missed one. Maintaining a consistent dosing schedule is vital for therapeutic efficacy and safety monitoring.
Overdose
Symptoms: Profound drowsiness, sedation, delirium, coma, tachycardia, hypotension, respiratory depression, hypersalivation, and seizures are common. Aspiration pneumonia and cardiac arrhythmias are serious risks.
Management: There is no specific antidote. Management is supportive and symptomatic. Ensure a patent airway and assist ventilation if necessary. Continuous cardiac monitoring is essential. Gastric lavage may be considered if presented early. Administering activated charcoal can be beneficial. Management of hypotension and arrhythmias should follow advanced cardiac life support protocols. Seizures should be managed with benzodiazepines.
Storage
Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). Dispense in the original, well-closed, light-resistant container to protect from moisture and light. Keep out of reach of children and pets.
Disclaimer
This information is for educational and professional medical purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. The prescribing healthcare professional is responsible for determining the appropriate dosage and monitoring regimen for each individual patient, strictly in accordance with the official Prescribing Information and the requirements of the Clozapine REMS Program. Always consult the full FDA-approved labeling before prescribing.
Reviews
“Clozaril has been a transformative agent in my practice for managing treatment-resistant schizophrenia. While the monitoring requirements are stringent, the payoff in terms of symptom reduction and functional improvement in this difficult-to-treat population is unparalleled. It demands respect and vigilance, but it is often the only drug that works.” – Psychiatrist, 15 years of experience.
“In our clinical trials unit, Clozaril remains the gold standard against which other antipsychotics for treatment-resistant cases are measured. Its unique efficacy profile is undeniable, though its side effect burden necessitates a highly structured and collaborative approach to patient care between psychiatrists, primary care, and the patients themselves.” – Clinical Researcher, Psychiatry.