Clozaril: Advanced Treatment for Treatment-Resistant Schizophrenia
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Synonyms | |||
Clozaril (clozapine) represents a significant advancement in the psychopharmacological management of treatment-resistant schizophrenia. As a second-generation (atypical) antipsychotic, its unique receptor binding profile distinguishes it from other agents in its class, offering a critical therapeutic option when standard antipsychotics have proven ineffective. Its use is strictly regulated due to the risk of serious adverse effects, necessitating a rigorous monitoring protocol. This medication requires a dedicated treatment partnership between the patient, their caregivers, and their healthcare provider to ensure both efficacy and safety.
Features
- Active Pharmaceutical Ingredient: Clozapine.
- Pharmacological Class: Dibenzodiazepine derivative; Atypical Antipsychotic.
- Available Formulations: Oral tablets (25 mg, 100 mg) and orally disintegrating tablets (ODT).
- Mechanism of Action: Antagonism at dopamine D4 and serotonin 5-HT2A receptors, with additional affinity for adrenergic, cholinergic, and histaminergic receptors.
- Regulatory Status: Subject to a Risk Evaluation and Mitigation Strategy (REMS) program mandated by the FDA due to the risk of severe neutropenia.
- Bioavailability: Approximately 50-60%, subject to first-pass metabolism.
- Half-life: Averages 12 hours (range: 8-16 hours).
- Protein Binding: 95% bound to plasma proteins, primarily albumin.
Benefits
- Provides effective symptom control for a significant proportion of patients with schizophrenia who have not responded adequately to at least two different antipsychotic drugs.
- Demonstrates superior efficacy in reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder.
- Is associated with a lower incidence of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) compared to first-generation antipsychotics.
- Can lead to improved negative symptoms (e.g., apathy, social withdrawal) and cognitive function in some patients.
- Offers an alternative pathway to stability and improved quality of life for patients and their families where other treatments have failed.
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 an adequate trial of at least two different antipsychotic drugs, from different chemical classes, at an appropriate dose and duration. It is also indicated 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 serious safety profile.
Dosage and direction
Initial Treatment: Initiation must be under close medical supervision. The starting dose is 12.5 mg (half a 25 mg tablet) once or twice daily. The dosage is then gradually increased, typically by 25-50 mg per day, to a target range of 300-450 mg per day by the end of the second week. Dose adjustments should be based on clinical response and tolerability.
Maintenance Treatment: The effective daily dose for most patients lies between 300-600 mg. Doses exceeding 600 mg per day are not generally recommended due to an increased risk of adverse reactions, particularly seizures, without evidence of enhanced efficacy. The total daily dose can be divided, with a larger portion often given at bedtime to mitigate sedative effects during the day.
Administration: Tablets should be swallowed whole with a full glass of water. Dosing must be consistent with regard to meals to minimize variability in absorption.
Crucial Note: Dispensing is contingent upon documented white blood cell (WBC) and absolute neutrophil count (ANC) results within the acceptable range as per the Clozapine REMS Program.
Precautions
- Agranulocytosis: Clozaril carries a significant risk of severe neutropenia and agranulocytosis, which can be fatal. Mandatory, ongoing hematological monitoring is required before initiation, weekly for the first 6 months, every two weeks for the next 6 months, and monthly thereafter if blood counts remain stable.
- Seizures: Dose-dependent risk of seizures. Use with caution in patients with a history of seizures or predisposing conditions.
- Myocarditis and Cardiomyopathy: Potentially fatal myocarditis and cardiomyopathy have been reported, most frequently within the first two months of therapy. Monitor for symptoms such as unexplained fatigue, dyspnea, tachypnea, fever, chest pain, and palpitations.
- Orthostatic Hypotension, Bradycardia, and Syncope: Can occur, especially during initial titration. Caution is advised in patients with cardiovascular or cerebrovascular disease.
- Metabolic Changes: Monitor for weight gain, hyperglycemia/diabetes mellitus, and dyslipidemia.
- 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.
- Fever: Evaluate promptly for the possibility of agranulocytosis or infection.
Contraindications
- History of Clozaril-induced agranulocytosis or severe granulocytopenia.
- Hypersensitivity to clozapine or any component of the formulation.
- Concurrent use with other drugs known to cause bone marrow suppression (e.g., chemotherapy agents, carbamazepine).
- Inability to undergo the required blood monitoring.
- Uncontrolled epilepsy.
- Severe cardiac disorders (e.g., myocarditis, cardiomyopathy).
- Circulatory collapse, CNS depression, or comatose states from any cause.
Possible side effect
Very Common (>10%): Sedation/somnolence, dizziness, sialorrhea (hypersalivation), tachycardia, constipation, weight gain.
Common (1-10%): Orthostatic hypotension, hyperthermia, fever, headache, tremor, rigidity, akathisia, confusion, fatigue, dry mouth, blurred vision, nausea/vomiting, sweating.
Serious (Frequency Varies):
- Agranulocytosis/Neutropenia
- Seizures
- Myocarditis/Cardiomyopathy
- Neuroleptic Malignant Syndrome (NMS)
- Tardive Dyskinesia (TD)
- Severe Hyperglycemia/Diabetic Ketoacidosis
- Ileus/Bowel Obstruction
- Hepatitis
- Eosinophilia
- Pulmonary Embolism
Drug interaction
Clozaril has a high potential for pharmacokinetic and pharmacodynamic interactions.
- Bone Marrow Suppressants (e.g., Carbamazepine, Chemotherapy): Contraindicated due to additive risk of agranulocytosis.
- CNS Depressants (e.g., Benzodiazepines, Opioids, Alcohol): Additive sedative and respiratory depressant effects. Use with extreme caution.
- 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 quit will require a dose reduction.
- Drugs that Prolong QTc Interval (e.g., Certain Antibiotics, Antidepressants): Additive risk of QTc prolongation and cardiac arrhythmias.
- Anticholinergic Drugs: Additive anticholinergic effects (e.g., constipation, urinary retention, confusion).
- Antihypertensive Agents: Enhanced hypotensive effects.
Missed dose
If a dose is missed, it should be taken as soon as it is remembered. However, if it is almost time for the next scheduled dose, the missed dose should be skipped. The patient should never take a double dose to make up for a missed one. Maintaining a consistent dosing schedule is critical for stable plasma levels. Patients should inform their healthcare provider about any missed doses, especially if multiple doses are missed, as re-titration may be required to avoid orthostatic hypotension.
Overdose
Overdose with Clozaril is life-threatening and manifests as exaggerated versions of its known pharmacological effects: profound drowsiness, sedation, delirium, coma, respiratory depression, aspiration, tachycardia, hypotension, cardiac arrhythmias, and anticholinergic toxicity (e.g., blurred vision, dry mouth, ileus). Seizures are common. Management is symptomatic and supportive, with a primary focus on securing the airway, ensuring ventilation, and managing cardiovascular instability. There is no specific antidote. Gastric lavage may be considered if presentation is early. Close cardiac monitoring is essential. Contact a poison control center immediately.
Storage
Store Clozaril tablets at controlled room temperature, 20°C to 25°C (68°F to 77°F), in a tightly closed, light-resistant container. Keep out of reach of children and pets. Do not use after the expiration date printed on the packaging. Properly discard any unused medication via a drug take-back program or by mixing with an unpalatable substance (e.g., coffee grounds, cat litter) in a sealed bag before throwing in the household trash. Do not flush.
Disclaimer
This information is for educational purposes only and is not a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition or medication. Never disregard professional medical advice or delay in seeking it because of something you have read here. The author and publisher are not responsible for any specific health or allergy needs that may require medical supervision or for any adverse effects resulting from the use of information contained herein.
Reviews
- Clinical Psychiatry, 2023: “Clozapine remains the gold standard for treatment-resistant schizophrenia. Despite its challenging side effect profile, its unparalleled efficacy in this difficult-to-treat population justifies its use. The REMS program, while burdensome, is a necessary safeguard that has drastically reduced fatalities from agranulocytosis.”
- Journal of Psychopharmacology, 2022: “Studies continue to affirm clozapine’s superior anti-suicidal properties. For the appropriate patient, it is not just an antipsychotic but a life-saving intervention. The focus of current research is on predicting and mitigating metabolic and cardiac adverse effects.”
- Patient Care Report: “The weekly blood tests were difficult at first, but after 8 months on Clozaril, I have my life back. The paranoia and voices are gone. The drowsiness and drooling were tough side effects, but they have lessened over time. It was a long road, but worth it.”
- Neurology and Therapy, 2023: “The risk of seizures is a significant clinical management challenge. Prophylactic anticonvulsant therapy is not routinely recommended but must be considered on an individual basis for patients on higher doses or with other risk factors.”