Clozapine Tablet Package Insert

Clozapine Tablet Package Insert (Simplified Version)

Please read the instructions carefully and use under the guidance of a physician.
Warning Statement
1. Agranulocytosis: Clozapine carries a high risk of inducing agranulocytosis, a serious, life-threatening adverse reaction that can lead to severe infections and death. Therefore, clozapine is indicated only for the treatment of refractory schizophrenia in patients who have failed adequate-dose, full-course therapy with at least two different antipsychotic agents. Patients receiving clozapine must undergo baseline white blood cell (WBC) count and absolute neutrophil count (ANC) assessments prior to initiating treatment, with regular follow-up monitoring during therapy: weekly for the first six months after starting medication; if results remain normal, frequency may be reduced to every two weeks for the subsequent six months; if results continue to be normal, follow-up can then be conducted every four weeks; and for at least four weeks after discontinuation, weekly monitoring is required. During treatment, patients are advised to promptly report any symptoms suggestive of severe neutropenia or infection, such as fever, weakness, somnolence, or sore throat. Clozapine should be used only under the supervision of a physician with appropriate prescribing authority or a specialist. (See the “Precautions” section for specific warnings.)
     
2. Seizures: Clozapine may precipitate seizures, with the risk being dose-dependent—higher doses are associated with a greater likelihood of seizure occurrence. Treatment with this medication should be initiated at a low dose, with gradual dose escalation and administration in divided doses. Patients with a history of seizures or other predisposing factors (such as central nervous system disorders, concomitant use of other seizure-inducing medications, or alcohol abuse) should use clozapine with caution. Patients should be advised to avoid activities that could pose a risk to themselves or others due to sudden loss of consciousness.

3. Orthostatic Hypotension, Bradycardia, Syncope, and Other Cardiovascular and Respiratory Adverse Reactions Clozapine may cause orthostatic hypotension and bradycardia, with or without syncope; in very rare cases, severe hypotensive collapse accompanied by respiratory and/or cardiac arrest has been reported. Orthostatic hypotension most often occurs during rapid dose escalation from the initial dose. Patients with cardiovascular or cerebrovascular disease, or those prone to hypotension (e.g., due to dehydration or concomitant use of antihypertensive medications), should use clozapine with caution. When patients who have discontinued clozapine for a brief interval (e.g., 2 days or longer) resume treatment, the initial dose should be 12.5 mg once or twice daily. There have been reports of hypotensive collapse, respiratory arrest, and cardiac arrest in patients who were concurrently taking benzodiazepines or other antipsychotic agents; therefore, special caution is warranted when initiating clozapine in patients already receiving such medications (see the warning under “Precautions” for details).

4. Myocarditis, Cardiomyopathy, and Mitral Valve Dysfunction Postmarketing safety data indicate that clozapine increases the risk of fatal myocarditis and cardiomyopathy, particularly (but not limited to) during the first month of treatment. Symptoms of cardiomyopathy typically appear later than those of clozapine-associated myocarditis and usually develop after 8 weeks of therapy. Myocarditis and cardiomyopathy can occur at any time during clozapine treatment. If patients present with chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or electrocardiographic abnormalities, the possibility of myocarditis or cardiomyopathy should be considered. There have been case reports of mitral valve dysfunction associated with clozapine use, with mild to moderate mitral regurgitation observed on two-dimensional echocardiography in these cases. Once myocarditis or cardiomyopathy is suspected, clozapine should be discontinued immediately and the patient referred to a specialist; patients who have experienced clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with clozapine. (See the warning under “Precautions” for further details.)

5. Increased Mortality in Elderly Patients with Dementia-Related Psychosis The risk of mortality is increased when elderly patients with dementia-related psychosis are treated with atypical antipsychotics such as clozapine. Clozapine tablets are not approved for the treatment of psychosis associated with dementia (see the warning under “Precautions” for details).

Drug Introduction

【Drug Name】 Generic Name: Clozapine Tablets English Name: Clozapine Tablets Pinyin: Lüdanping Pian
     
【Ingredients】The active ingredient of this product is clozapine. Its chemical name is 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine.
     
【Characteristics】This product is a pale yellow tablet.
     
【Indications】This product is effective not only for the positive symptoms of schizophrenia but also for its negative symptoms. It is indicated for all subtypes of acute and chronic schizophrenia, with particularly good efficacy in the hallucinatory–delusional and hebephrenic types. It can also alleviate affective symptoms associated with schizophrenia, such as depression, guilt, and anxiety. For some patients who have failed to respond or have shown poor response to conventional antipsychotic medications, switching to this product may be effective. This product is also used to treat agitation, excitement, and hallucinatory–delusional symptoms in mania or other psychotic disorders. However, due to its potential to cause agranulocytosis, it is generally not recommended as a first-line agent.
     
【Specification】25 mg 【Dosage and Administration】Oral administration. Start with a low dose: the initial dose is 25 mg (1 tablet) once, 2 to 3 times daily, and gradually and slowly increase to the usual therapeutic dose of 200–400 mg (8–16 tablets) per day; the maximum dose may be up to 600 mg (24 tablets) per day. The maintenance dose is 100–200 mg (4–8 tablets) per day.
     
【Adverse Reactions】 Common adverse reactions include: central nervous system reactions such as somnolence, sedation, dizziness, vertigo, headache, and tremor; cardiovascular reactions such as tachycardia, hypotension, orthostatic hypotension, and syncope; autonomic nervous system reactions such as hyperactivity, salivation, sweating, excessive perspiration, dry mouth, and visual disturbances; gastrointestinal reactions such as constipation, nausea, and vomiting; and other reactions such as weakness, fever, increased appetite, and weight gain. With continued treatment or dose reduction, complaints of somnolence, sedation, and salivation (particularly during sleep) may diminish. It may also cause electrocardiographic abnormalities and changes in the electroencephalogram or epileptic seizures. Hyperglycemia may also occur. Serious adverse reactions include agranulocytosis and secondary infections.
     
Adverse reactions/events identified in clinical trials of clozapine or detected during post-marketing surveillance:
Central Nervous System
Drowsiness, sedation, dizziness, vertigo, headache, tremor, syncope, sleep disturbances, nightmares, restlessness, impaired motor function, movement disorders, agitation, epilepsy (seizures), rigidity, akathisia, consciousness disturbance, fatigue, insomnia, hyperkinesia, weakness, ataxia, dysarthria, depression, anxiety, mutism, delirium, convulsions, ataxia, delusions, hallucinations, involuntary movements, stuttering, speech articulation disorder, amnesia/memory loss, stereotyped behavior, increased or decreased libido, paranoia, tremor, Parkinsonism, irritability, delirium, exacerbation of schizophrenia, myoclonus, overdose toxicity, sensory disturbances, mild cataplexy, status epilepticus.
     
Cardiovascular System
Tachycardia, hypotension, orthostatic hypotension, hypertension, chest pain, angina pectoris, electrocardiographic abnormalities, edema, palpitations, thrombophlebitis, deep vein thrombosis, cyanosis, ventricular premature beats, QT interval prolongation, torsades de pointes, atrial fibrillation, ventricular fibrillation, bradycardia, syncope, peripheral tissue edema, myocarditis, and cardiomyopathy.
     
Digestive System
Constipation, abdominal discomfort, heartburn, nausea, vomiting, diarrhea, abnormal liver function, anorexia, bloating, gastroenteritis, rectal bleeding, gastroparesis, fecal abnormalities, hematemesis, gastric ulcer, bitter taste in the mouth, belching, acute pancreatitis, dysphagia, fecal impaction, paralytic ileus, salivary gland swelling, colitis, cholestasis, hepatitis, and jaundice.
     
Urinary and Reproductive System
Urinary abnormalities, urinary incontinence, ejaculatory dysfunction, urinary urgency, urinary frequency, urinary retention, dysmenorrhea, erectile dysfunction, vaginal pruritus, acute interstitial nephritis, and priapism.
     
Autonomic Nervous System
Drooling, excessive sweating, dry mouth, visual disturbances, numbness, polydipsia, hot flashes, dry throat, and mydriasis.
     
Skin
Rash, pruritus, pallor, eczema, erythema, bruising, dermatitis, purpura, urticaria. Allergic reactions: photosensitive dermatitis, vasculitis, erythema multiforme, Stevens-Johnson syndrome.
     
Musculoskeletal System
Muscle weakness, pain (in the back, neck, and legs), muscle spasms, myalgia, fasciculations, arthralgia, myasthenic syndrome, and rhabdomyolysis.
     
Respiratory System
Pharyngeal discomfort, dyspnea, tachypnea, nasal congestion, epistaxis, cough, pneumonia-like symptoms, rhinorrhea, hyperventilation, stridor, bronchitis, laryngitis, sneezing, aspiration, and pleural effusion.
     
Blood/Lymphatic System
Leukopenia, neutropenia, agranulocytosis, eosinophilia, anemia, leukocytosis, elevated hemoglobin, increased hematocrit, accelerated erythrocyte sedimentation rate, pulmonary embolism, sepsis, thrombocytosis, and thrombocytopenia.
     
Metabolic and Nutritional Disorders
Weight gain, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, ketoacidosis, hyperosmolar coma or death, hyperuricemia, hyponatremia, and weight loss.
     
Extrapyramidal symptoms:
Extrapyramidal symptoms manifest as acute dystonia, characterized by forced mouth opening, protrusion of the tongue, torticollis, respiratory dysfunction, and dysphagia; parkinsonian syndromes such as increased muscle tone, a mask-like facial expression, bradykinesia, tremor, and salivation; akathisia; and tardive dyskinesias, including sucking, tongue licking, and chewing.
     
Symptoms of dystonia manifest as abnormally prolonged muscle contractions and may occur in susceptible patients during the first few days of pharmacotherapy. Dystonic symptoms include neck muscle spasms, which sometimes present as progressive pharyngeal tightness, dysphagia, dyspnea, and/or protrusion of the tongue. Once these symptoms develop while taking low-dose typical antipsychotics, the likelihood of their occurrence at higher doses—and the severity of such symptoms—increases. A heightened risk of acute dystonia has been observed in younger male patients. The incidence of dystonia with clozapine is extremely low. (See the warning under “Precautions” for further details.)
     
Other reactions
Fever, chills, hypothermia, malaise, increased appetite, ear disorders, eyelid disorders, ocular hyperemia, nystagmus, angle-closure glaucoma, elevated creatine kinase, neuroleptic malignant syndrome, relapse of psychosis after discontinuation of medication, and cholinergic rebound.
     
【Contraindications】 Do not use in patients with severe cardiac, hepatic, or renal disease, delirium, hypotension, or glaucoma.
Contraindicated in patients with hypersensitivity to clozapine or any of its other components; contraindicated in patients with bone marrow dysplasia; contraindicated in patients with inadequately controlled epilepsy; contraindicated in patients with paralytic ileus; contraindicated in patients who have previously developed agranulocytosis or severe granulocytopenia due to clozapine; contraindicated in patients with leukopenia; and, similar to typical antipsychotics, contraindicated in patients with severe central nervous system depression or in a comatose state due to any cause. Concurrent use with other drugs that may cause agranulocytosis or exert bone marrow-suppressive effects is also contraindicated.