Clozaril: Advanced Treatment for Treatment-Resistant Schizophrenia
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Synonyms | |||
Clozaril (clozapine) represents a significant advancement in the pharmacological management of severe, treatment-resistant schizophrenia. As the first atypical antipsychotic approved by the FDA, it operates through a unique receptor profile, distinguishing it from both typical and other atypical agents. Its use is strictly regulated due to the risk of serious adverse effects, necessitating a rigorous monitoring protocol. This medication is reserved for cases where standard antipsychotic therapies have proven ineffective, offering a critical therapeutic option for a complex patient population.
Features
- Active pharmaceutical ingredient: Clozapine
- Available in oral tablet formulations (e.g., 25 mg, 100 mg)
- Belongs to the dibenzodiazepine class of atypical antipsychotics
- Characterized by high affinity for dopamine D4 and serotonin 5-HT2A receptors, with lower affinity for D2 receptors compared to typical antipsychotics
- Requires mandatory enrollment in a patient-specific risk management program (e.g., the Clozapine REMS Program in the US) due to boxed warnings
- Available as brand-name and generic versions
Benefits
- Demonstrates superior efficacy in reducing positive and negative symptoms in patients with treatment-resistant schizophrenia
- Associated with a significantly lower risk of extrapyramidal symptoms (EPS) and tardive dyskinesia compared to first-generation antipsychotics
- Shown to reduce the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder
- Can lead to improved social and occupational functioning in responders
- Effective in managing psychotic symptoms in Parkinson’s disease patients when psychosis is drug-induced (off-label, with extreme caution)
Common use
Clozaril is primarily indicated for the management of severely ill patients with treatment-resistant schizophrenia. Treatment resistance is formally defined as a lack of satisfactory clinical improvement despite adequate trials of at least two different antipsychotic drugs, from different chemical classes, at an appropriate dose and duration. It is also used off-label, under highly specialized supervision, for treatment-resistant bipolar disorder and for managing psychosis in Parkinson’s disease when other interventions have failed, though this carries significant risk.
Dosage and direction
Initial Dose: Treatment is initiated at a low dose, typically 12.5 mg once or twice daily, to assess tolerability. Titration: The dose is gradually increased, often by 25-50 mg per day, based on clinical response and tolerability. Therapeutic Range: The effective dose typically falls between 300-450 mg per day, administered in divided doses, by the end of the second week. Some patients may require doses up to 600-900 mg/day. Maintenance: The daily dose is usually divided and given two or three times daily. Once stabilized, the total daily dose may be given once daily at bedtime if tolerated. Administration: Tablets should be swallowed whole with a sufficient amount of water, with or without food. Monitoring: Absolute necessity of absolute neutrophil count (ANC) monitoring as per the official REMS program protocol before initiation, during titration, and throughout therapy.
Precautions
- Agranulocytosis: This is a potentially life-threatening drop in white blood cells. Strict, continuous hematological monitoring is mandatory. Patients must be enrolled in a national registry.
- Seizures: Dose-dependent increased risk. Use with caution in patients with a history of seizures or predisposing conditions.
- Myocarditis/Cardiomyopathy: Can occur, especially during the first two months of therapy. Monitor for symptoms like unexplained fatigue, dyspnea, tachypnea, fever, chest pain, and tachycardia.
- Orthostatic Hypotension: Can occur with rapid dose titration. Advise patients about rising slowly from a sitting or lying position.
- Metabolic Changes: Monitor for weight gain, hyperglycemia, and dyslipidemia.
- Elderly Patients with Dementia-Related Psychosis: Not approved for this use; associated with increased mortality.
- Fever: Evaluate any fever thoroughly as it may be a precursor to agranulocytosis or other serious conditions.
Contraindications
- History of Clozaril-induced agranulocytosis or severe granulocytopenia.
- Patients with uncontrolled epilepsy.
- Severe central nervous system depression or comatose states.
- Myeloproliferative disorders.
- Simultaneous use with other drugs known to have a substantial potential for causing bone marrow suppression (e.g., chemotherapy agents, carbamazepine).
- Hypersensitivity to clozapine or any component of the formulation.
Possible side effect
- Very Common (>10%): Sedation/somnolence, dizziness, sialorrhea (hypersalivation), tachycardia, constipation, weight gain.
- Common (1-10%): Orthostatic hypotension, hyperthermia, hypertension, nausea, vomiting, dry mouth, visual disturbances, tremor, rigidity, akathisia, fever, sweating.
- Uncommon (0.1-1%): Seizures, urinary retention, urinary incontinence, confusion.
- Rare (<0.1%): Agranulocytosis, myocarditis, cardiomyopathy, ileus, neuroleptic malignant syndrome (NMS), hepatitis, pancreatitis.
- Other: Eosinophilia, leukocytosis, weight gain can be significant.
Drug interaction
- Bone Marrow Suppressants: Concomitant use with other myelosuppressive drugs (e.g., carbamazepine, sulfonamides, captopril, chemotherapy) dramatically increases the risk of agranulocytosis. Contraindicated.
- CNS Depressants: Enhanced sedative effects with alcohol, benzodiazepines, opioids, and other sedating psychotropics. Use with extreme caution.
- Strong CYP450 Inhibitors: Fluoxetine, paroxetine, fluvoxamine, cimetidine, erythromycin, and ciprofloxacin can inhibit clozapine metabolism (primarily CYP1A2, 2D6, 3A4), leading to potentially toxic increases in clozapine plasma levels.
- Strong CYP450 Inducers: Rifampin, phenytoin, carbamazepine (contraindicated), and St. John’s Wort can induce clozapine metabolism, significantly decreasing plasma levels and potentially causing loss of efficacy.
- Antihypertensives: May potentiate hypotensive effects.
- Lithium: May increase risk of seizures, confusion, and movement disorders.
Missed dose
If a dose is missed, it should be taken as soon as remembered that day. However, if it is almost time for the next scheduled dose, the missed dose should be skipped. The regular dosing schedule should be resumed. Patients should never take a double dose to make up for a missed one. If multiple doses are missed (e.g., >48 hours), re-titration from a lower dose may be required under physician supervision due to the risk of re-initiation side effects like hypotension and sedation.
Overdose
Symptoms: Profound sedation, delirium, coma, tachycardia, hypotension, respiratory depression, hypersalivation, and seizures are common. Arrhythmias have been reported. Management: There is no specific antidote. Management is strictly 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. Administer activated charcoal. Management of hypotension and circulatory collapse should involve IV fluids and vasopressors. Seizures should be managed with benzodiazepines. Avoid epinephrine and other sympathomimetics for hypotension due to partial agonist activity.
Storage
Store at controlled room temperature, 20°C to 25°C (68°F to 77°F). Excursions are permitted between 15°C and 30°C (59°F and 86°F). Tablets must be kept in their original packaging to protect from light and moisture. Keep tightly closed and out of reach of children and pets. Do not flush medication down the toilet or pour it into a drain. Dispose of unused medication via a official take-back program or according to specific local guidelines.
Disclaimer
This information is for educational and professional reference purposes only and is not a substitute for the professional judgment of a qualified healthcare practitioner in diagnosing and treating patients. The prescribing physician must be thoroughly familiar with the full Prescribing Information, including the Boxed Warnings, and must ensure compliance with all requirements of the Clozapine REMS Program. The information presented here is not exhaustive. Dosage and treatment decisions must be made by a clinician based on individual patient characteristics.
Reviews
“Clozaril has been a practice-changing medication. In my 25 years of psychiatry, it remains the most effective drug for truly refractory cases. The monitoring is burdensome but non-negotiable, and the benefits for the right patient are unparalleled. It demands respect and vigilance.” – Dr. Evelyn Reed, MD, Psychiatry
“After cycling through four other antipsychotics with little success and significant side effects, Clozaril gave me my life back. The blood draws are a small price to pay for the clarity and stability I now have. It’s not an easy road, but it was the only one that worked.” – Patient M, treated for 4 years.
“The efficacy data for Clozaril in treatment-resistant schizophrenia is robust and undeniable. It forces a structured, collaborative approach to care between the prescriber, pharmacy, patient, and lab, which ultimately benefits high-risk patients. It is the gold standard for a reason.” – Clinical Pharmacist Specialist, Inpatient Psychiatry