Approval Date.
Clozapine Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Warnings
1. Granulocyte deficiency
Because clozapine has a high risk of triggering granulocyte deficiency, which is a serious life-threatening adverse reaction that can lead to serious infection and death. Therefore, clozapine is indicated only for the treatment of patients with refractory schizophrenia who have failed to respond to a full course of at least 2 different antipsychotics in full dosage.
Patients treated with clozapine must have a baseline white blood cell count (WBC) and absolute neutrophil count (ANC) before starting treatment and be reviewed regularly during treatment, weekly for the first 6 months after dosing; if normal, the frequency may be reduced to every 2 weeks for the next 6 months, and if the results remain normal, the frequency may be reduced to every 4 weeks thereafter; after discontinuation If the results are still normal, the frequency may be reduced to once every 4 weeks thereafter. Patients are advised to report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat) immediately while on medication. Clozapine should be used by a physician with appropriate prescribing qualifications or under the supervision of a specialist. (See warnings under [Precautions] for details).
2. Seizures
Clozapine can cause seizures and the risk is dose-related, with higher doses being more likely to occur. Use of this product should be started with a small dose, gradually increasing the dose, and divided into smaller doses. Clozapine should be used with caution in patients with a history of seizures or other predisposing factors (e.g., central nervous system disease, use of other seizure-inducing drugs, alcohol abuse). Patients should be advised to avoid activities that pose a risk to themselves or others due to sudden loss of consciousness.
3. Postural hypotension, bradycardia, syncope, and other cardiovascular and respiratory adverse reactions
Clozapine may cause postural hypotension and bradycardia with or without syncope, and in rare cases, severe hypovolemia with respiratory and/or cardiac arrest. Postural hypotension tends to occur during rapid dose increases from the initial dose. Clozapine should be used with caution in patients with cardiovascular or cerebrovascular disease or who are prone to hypotensive conditions (e.g., dehydration, use of antihypertensive medications).
Patients who have experienced a short interval (e.g., 2 or more days) while taking clozapine should be given a starting dose of 12.5 mg once or twice a day when taking the drug again.
Defibrillation, respiratory arrest, and cardiac arrest have been reported in patients during the initiation of benzodiazepines or other antipsychotics, so special caution should be exercised when clozapine is started in patients taking benzodiazepines or other antipsychotics (see warnings under [Precautions] for details).
4. Myocarditis, cardiomyopathy, and mitral valve insufficiency
Analysis of post-marketing safety data indicates that clozapine has an increased risk of fatal myocarditis and cardiomyopathy, particularly (but not exclusively) during the first month of dosing. Symptoms of cardiomyopathy usually occur later than clozapine-associated myocarditis and usually occur after 8 weeks of treatment. Myocarditis and cardiomyopathy can occur at any time during treatment with clozapine. The possibility of myocarditis or cardiomyopathy should be considered if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or electrocardiographic changes occur. Cases of mitral valve insufficiency due to clozapine administration have been reported with mild or moderate mitral regurgitation on 2D echocardiograms.
Patients with suspected myocarditis or cardiomyopathy should discontinue clozapine immediately and be referred to a specialist, and patients with clozapine-associated myocarditis or cardiomyopathy should not be re-treated with clozapine. (See warning under [Precautions] for details).
5. Increased mortality in elderly patients with dementia-associated psychosis
There is an increased risk of death when clozapine and other atypical antipsychotics are used to treat elderly patients with dementia-associated psychosis. Clozapine tablets are not approved for the treatment of patients with dementia-related psychosis (see warning under [Precautions] for details).
Drug Name]
Generic Name: Clozapine Tablets
English name: Clozapine Tablets
Hanyu Pinyin: Lüdanping Pian
Ingredients
The main ingredient of this product is clozapine.
Chemical name: 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine
Its chemical structure formula is
Molecular formula: C18H19ClN4
Molecular weight: 326.84
【Properties】.
This product is a light yellow tablet.
Indications
Refractory schizophrenia.
Specification
25mg
Dosage]
Oral Start with a small dose of 25mg (1 tablet) for the first time, 2-3 times a day, and gradually increase to the usual therapeutic dose of 0.2-0.4g (8-16 tablets) a day, and up to 0.6g (24 tablets) a day. The maintenance dose is 0.1-0.2g (4-8 tablets) a day.
Adverse reactions
Common adverse reactions: central nervous system reactions, such as drowsiness, sedation, dizziness, vertigo, headache and tremor; cardiovascular reactions, such as tachycardia, hypotension and syncope; autonomic nervous system reactions, such as hyperactivity, salivation, sweating, dry mouth and visual disturbance; gastrointestinal reactions, such as constipation and nausea; other reactions, such as fever. Complaints of drowsiness, sedation, and salivation (especially during sleep) may decrease with continued treatment or dose reduction.
Adverse reactions/events identified in clinical trials of clozapine or identified by post-marketing surveillance.
Central nervous system
Drowsiness, sedation, dizziness, vertigo, headache, tremor, syncope, sleep disturbance, nightmares, fidgeting, hyperkinesia, dyskinesia, agitation, seizures (convulsions), rigidity, inability to sit still, disturbance of consciousness, fatigue, insomnia, hyperkinesia, weakness, drowsiness, ataxia, slurred speech, depression, anxiety, oligophrenia, confusion, convulsions, uncoordinated movements, delusions, hallucinations, un voluntary movements, stuttering, dysarthria, amnesia/memory loss, performance-like movements, increased or decreased libido, paranoia, tremors, Parkinson’s disease, irritability, delirium, increased schizophrenia, myoclonus, overdose, sensory abnormalities, mild sudden collapse, and persistent epilepsy.
Cardiovascular system
Tachycardia, hypotension, postural hypotension, hypertension, chest pain, angina pectoris, ECG abnormalities, edema, palpitations, thrombophlebitis, deep vein thrombosis, cyanosis, premature ventricular beats, prolonged QT interval, tip-twisting ventricular tachycardia, atrial fibrillation, ventricular fibrillation, bradycardia, syncope, peripheral tissue edema, myocarditis, cardiomyopathy.
Digestive system
Constipation, abdominal discomfort, heartburn, nausea, vomiting, diarrhea, abnormal liver function, anorexia, abdominal distension, gastroenteritis, rectal bleeding, gastric motor nerve disorder, fecal abnormalities, vomiting blood, gastric ulcer, bitter mouth, belching, acute pancreatitis, dysphagia, fecal impaction, paralytic intestinal obstruction, swollen salivary glands, colitis, bile depression, hepatitis, jaundice.
Genitourinary system
Urinary abnormalities, urinary incontinence, abnormal ejaculation, urinary urgency, urinary frequency, urinary retention, dysmenorrhea, impotence, vaginal itching, acute interstitial nephritis, abnormal penile erection.
Autonomic nervous system
Salivation, excessive sweating, dry mouth, visual disturbance, numbness, irritability, hot flashes, dry throat, dilated pupils.
Skin
Rash, pruritus, pallor, eczema, erythema, bruising, dermatitis, bruising, urticaria. Allergic reactions: photosensitivity dermatitis, vasculitis, erythema multiforme, Stevens-Johnson syndrome.
Musculoskeletal system
Muscle weakness, pain (back, neck, legs), muscle spasm, muscle pain, tremors, arthralgia, muscle weakness syndrome, rhabdomyolysis.
Respiratory system
Throat discomfort, dyspnea, shortness of breath, nasal congestion, rhinorrhea, cough, pneumonia-like symptoms, nasal overflow, hyperventilation, wheezing, bronchitis, laryngitis, sneezing, aspiration by mistake, pleural effusion.
Blood/Lymphatic System
Decreased white blood cell count, neutropenia, granulocyte deficiency, increased eosinophilia, anemia, leukocytosis, elevated hemoglobin, elevated hematocrit, increased hematocrit, pulmonary embolism, sepsis, thrombocytosis, thrombocytopenia.
Metabolic and nutritional disorders
Weight gain, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, ketoacidosis, hyperosmolar coma or death, hyperuricemia, hyponatremia, weight loss.
Extrapyramidal symptoms.
Extrapyramidal symptoms, manifesting as acute dystonia with forced mouth opening, tongue extension, slanting neck, respiratory dyskinesia and dysphagia; Parkinson’s syndrome-like symptoms such as increased muscle tone, dull face, slow movements, muscle tremor, salivation; inability to sit still; and delayed dyskinesia such as sucking, tongue licking and chewing.
Symptoms of dystonia, which manifests as abnormally prolonged contractions of muscle groups, may occur in those patients who are susceptible during the first few days of drug treatment. Symptoms of dystonia include muscle spasms in the neck, sometimes manifested as progressive throat tightening, dysphagia, dyspnea, and/or tongue protrusion. Once these symptoms occur at low doses of typical antipsychotics, there is a greater likelihood that they will occur more frequently and be more severe at higher doses. An increased risk of acute dystonia has been observed in younger male populations. The incidence of clozapine dystonia is extremely low. (See warnings under [Precautions] for details)
Other reactions
Fever, chills, hypothermia, malaise, increased appetite, ear infections, blepharopathy, ocular congestion, nystagmus, closed-angle glaucoma, elevated phosphocreatine kinase, nerve blocker malignant syndrome, recurrence of psychosis after discontinuation, cholinergic rebound.
Contraindication
Contraindicated in patients with severe cardiac, hepatic and renal disorders, hypotension, glaucoma.
Contraindicated in patients with hypersensitivity to clozapine or other components of clozapine.
Contraindicated in patients with myelodysplasia.
contraindicated in patients with uncontrolled epilepsy
contraindicated in patients with paralytic intestinal obstruction
contraindicated in patients with previous granulocyte deficiency or severe granulocytopenia due to clozapine
Similar to typical antipsychotics, it is contraindicated in patients with severe CNS depression or in coma from various causes.
Not to be used in combination with other drugs that cause granulocyte deficiency or myelosuppressive effects.
Precautions]
The addition of warnings under [Precautions] shall include.
Warnings
1. Granulocyte deficiency.
Clozapine is associated with a high risk of granulocyte deficiency, a serious life-threatening adverse reaction that can lead to serious infection and death. The risk of neutropenia is greatest during the first 18 weeks of treatment and then declines. The mechanism by which clozapine causes neutropenia is not known and is not dose-dependent. Therefore, clozapine is indicated only for refractory schizophrenia after a full dose and duration of treatment with at least 2 different antipsychotics, because of lack of efficacy, or because of intolerable adverse effects.
Clozapine should be used by a physician with appropriate prescribing qualifications or under the supervision of a specialist. White blood cell counts and classifications should be checked every 1 week for the first 6 months after administration and periodically thereafter. (Patients treated with clozapine should have a baseline white blood cell count and absolute neutrophil count performed prior to treatment and weekly for the first 6 months of treatment. If the WBC and absolute neutrophil count results are in compliance (WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3) during the first 6 months of treatment, the WBC and absolute neutrophil count may be checked every 2 weeks for the next 6 months of treatment. If the WBC and absolute neutrophil count results are in compliance during these 6 months (WBC ≥ 3500/mm3, ANC ≥ 2000/mm3), they may be checked every 4 weeks thereafter.)
If clozapine therapy is discontinued (for any reason), the white blood cell count and absolute neutrophil values should be checked weekly for at least 4 weeks after discontinuation until WBC ≥ 3500/mm3 and ANC ≥ 2000/mm3 are achieved. monitoring of the white blood cell count and absolute neutrophil values should be ensured before the next drug is given to the patient. Patients who develop drowsiness, weakness, fever, sore throat, or other signs of infection during clozapine therapy should be reported to the physician immediately.
2. Seizures.
In a premarketing clinical trial study of 1,743 subjects, 61 subjects had at least 1 seizure (incidence of approximately 3.5%). Based on that trial, the cumulative incidence of seizures at 1 year on clozapine was approximately 5%. The incidence was dose-dependent, with a higher incidence at higher doses. Clozapine should be used with caution in patients with a history of seizures or other predisposing factors (e.g., central nervous system disease, use of other seizure-inducing drugs, alcohol abuse). Because of the serious, seizure-inducing risk of clozapine, patients should be advised to avoid activities that pose a risk to themselves or others due to sudden loss of consciousness (e.g., operating complex machinery, driving a car, swimming, hiking, etc.).
3. Postural hypotension, bradycardia, syncope and other cardiovascular and respiratory adverse effects:
Clozapine may cause postural hypotension and bradycardia with or without syncope, and in rare patients severe hypotension with respiratory and/or cardiac arrest. Postural hypotension tends to occur during rapid dose increases from the initial dose. Use clozapine with caution in patients with cardiovascular or cerebrovascular disease or who are prone to hypotensive conditions (e.g., dehydration, use of anti-hypertensive medications).
Postural hypotension with or without syncope occurs with clozapine therapy and can be a persistent hazard in some patients. In rare cases (occurring at an incidence of approximately 1/3,000), severe hypovolemia with respiratory and/or cardiac arrest may occur. Postural hypotension occurs most often during rapid dose increases from the starting dose and can also occur during the administration of the first dose. One patient was reported to have experienced collapse and respiratory arrest at the starting dose of 12.5 mg. For patients who have had a short interval (e.g., 2 or more days) between doses of clozapine, it is recommended to start with 12.5 mg once or twice a day when taking the drug again.
Patients taking benzodiazepines for initial treatment may sometimes experience fainting, respiratory arrest, or cardiac arrest; similar conditions can occur with other antipsychotics or with clozapine. Although it is not known whether clozapine interacts with benzodiazepines or other antipsychotics, clozapine should be used with caution when patients are taking benzodiazepines or other antipsychotics.
Persistent tachycardia with an average increase in pulse rate of 10 to 15 beats per minute can occur in about 25% of patients taking clozapine. Persistent tachycardia is not just a reflex response to hypotension; it can be detected in a variety of positions. Both tachycardia and hypotension can pose serious risks in individuals with cardiac insufficiency.
Similar to other antipsychotics, clozapine can cause abnormal ECG repolarization, including S-T segment suppression, flattening, or T-wave inversion, in a small number of patients, which can be restored after discontinuation of the drug. The clinical significance of such changes is unclear. However, clinical trials of clozapine have shown that cardiovascular events, including ischemic changes, myocardial infarction, arrhythmias, and sudden death, can occur in some patients. In addition, congestive heart failure, pericarditis, and pericardial effusion have been reported in post-marketing clinical observations. Pre-existing cardiac disease and other possible causative factors make it difficult to determine the direct causative factors for these disorders. Sudden death has rarely been reported in patients with schizophrenia treated with or without antipsychotics, and the relationship between this and antipsychotic use is unclear.
Clozapine should be used with caution in patients with cardiovascular and/or pulmonary disease, and gradual titration of the dose and close observation is recommended.
4. Myocarditis, cardiomyopathy, and mitral valve insufficiency:
Analysis of post-marketing safety data indicates that clozapine has an increased risk of lethal myocarditis and cardiomyopathy, particularly (but not exclusively) during the first month of dosing. Symptoms of cardiomyopathy usually occur later than clozapine-associated myocarditis and usually occur after 8 weeks of treatment. Myocarditis and cardiomyopathy can occur at any time during treatment with clozapine.
The possibility of myocarditis may be suspected in patients taking clozapine who experience unexplained fatigue, dyspnea, shortness of breath, fever, chest pain, palpitations or other symptoms of heart failure, or abnormal ST-T waves or arrhythmias on the electrocardiogram. However, it is not clear whether eosinophilia implies the development of myocarditis. Tachycardia after clozapine application is also a manifestation of myocarditis. Therefore, monitoring for tachycardia during the first month of clozapine therapy is as important as monitoring for other symptoms of myocarditis. Patients with clozapine-associated myocarditis or cardiomyopathy should not be re-treated with clozapine as soon as myocarditis is suspected.
Once signs and symptoms of cardiomyopathy are detected, especially exertional dyspnea, fatigue, telangiectatic breathing, paroxysmal nocturnal dyspnea and peripheral tissue edema, then the clinician should be notified immediately and further investigations should be performed. In patients with confirmed cardiomyopathy, clozapine should be discontinued unless its efficacy far outweighs its risk.
Cases of mitral valve insufficiency have been reported with mild or moderate mitral regurgitation on 2D echocardiography as a result of clozapine administration.
5. Nerve blocker malignant syndrome (NMS):
Neuroblocker malignant syndrome is a complex, life-threatening disorder that can be caused by antipsychotics. Clinical manifestations include high fever, muscle tonicity, altered mental status, and autonomic dysregulation (irregular pulse rate or blood pressure, tachycardia, sweating, arrhythmias).
The diagnosis of neuronal blocker malignant syndrome is complex and has to be distinguished from signs and symptoms of severe medical illness (e.g., pneumonia, systemic infections, etc.) and untreated or inadequately treated extrapyramidal reactions (EPS), and also from toxic reactions to central antiparasympathetic effects, heat shock, pharmacogenic fever, and primary CNS disease.
The management of neural blocker malignant syndrome includes (1) immediate discontinuation of treatment with antipsychotics and other nonessential drugs, (2) intensive symptomatic treatment and clinical monitoring, and (3) special management of other serious complications. There is no consensus on whether to provide special management for non-serious neuraxial blocker malignant syndrome.
After recovery from neural blocker malignant syndrome, if the patient still needs antipsychotic treatment, the choice of drug should be cautious and should be closely monitored to prevent relapse.
Clozapine alone or in combination with lithium and other CNS-active drugs has also been reported to cause neuroblocker malignant syndrome.
6. Delayed-onset movement disorders:
Application of antipsychotic treatment can lead to delayed dyskinesia, an irreversible, involuntary movement disorder syndrome. The elderly, especially older women, are susceptible, but this does not allow for a clear formulation of a medication regimen for at-risk populations.
Many aspects suggest that the mechanism of delayed dyskinesia caused by clozapine differs from that of other antipsychotics. Preclinical studies have shown that clozapine has a weak dopamine receptor blocking effect, and clinical studies have shown that it causes a low incidence of certain acute extrapyramidal symptoms (e.g., dystonia). The etiology is difficult to determine because some patients have taken other antipsychotics and then developed delayed-onset dyskinesia after taking clozapine. There have been no reports of tardive dyskinesia with clozapine alone, but it does not prove that clozapine does not cause tardive dyskinesia.
The risk and incidence of tardive dyskinesia increases with duration of therapy and cumulative dose, and is irreversible. However, delayed-onset dyskinesia can occur in a few cases when treated with small doses and short courses of therapy. There is no definitive treatment for tardive dyskinesia, but symptoms may be partially or fully relieved after discontinuation of the medication. Antipsychotic treatment itself can suppress (or partially suppress) the symptoms of tardive dyskinesia, thereby masking its course. The mechanism of action of symptom suppression in the long-term course of late-onset movement disorders is unclear.
Based on these considerations, it is important to minimize the incidence of tardive dyskinesia when prescribing clozapine. As with other antipsychotics, clozapine may be chosen as a long-term maintenance medication in patients who have a good response to clozapine. Such patients should be treated with the shortest possible course of therapy and the lowest possible dose. If continued treatment is needed, periodic checkups should be performed and the treatment regimen should be redefined.
Patients taking clozapine who develop signs and symptoms of delayed dyskinesia may be considered for treatment interruption. However, some patients may require clozapine treatment despite the presence of symptoms of tardive dyskinesia.
7. Metabolic changes such as hyperglycemia, hyperlipidemia, and weight gain:
Atypical antipsychotics, including clozapine, have been identified to be associated with metabolic changes that may increase cardiovascular and cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and weight gain. While atypical antipsychotics may produce some metabolic changes, each drug in this class has its own specific risk profile.
Hyperglycemia and diabetes mellitus
Hyperglycemia has been reported in patients treated with atypical antipsychotics, including clozapine, with some of these patients eventually developing ketoacidosis, hyperosmolar coma, or death. The increased risk of developing diabetes in patients with schizophrenia and the increased incidence of diabetes in the general population make it difficult to evaluate the relationship between the administration of atypical antipsychotics and abnormal blood glucose, and therefore the relationship between the administration of atypical antipsychotics and other adverse effects caused by hyperglycemia is also unclear. However, epidemiological studies have shown that atypical antipsychotics can increase the incidence of hyperglycemia-induced adverse reactions and the risk of emergency management. The precise risk rate assessment of hyperglycemia induced by atypical antipsychotics is unclear.
Patients diagnosed with diabetes mellitus who are treated with atypical antipsychotics should be tested regularly to prevent further elevation of blood glucose. Patients with diabetes susceptibility factors (e.g., obesity, family history of diabetes) must have fasting glucose testing at the start and during treatment. Patients treated with atypical antipsychotics should be examined for symptoms of hyperglycemia, such as irritable thirst, polyuria, polyphagia and weakness. Once these symptoms are detected, patients must undergo fasting blood glucose testing. In some patients, symptoms of hyperglycemia disappear after discontinuation of atypical antipsychotic treatment; however, in some cases, diabetes treatment is required after discontinuation of the medication.
Weight gain can occur with the use of antipsychotics, including clozapine. Weight should be monitored during treatment with clozapine.
Dyslipidemia
Abnormal changes in dyslipidemia have been observed in patients treated with atypical antipsychotics. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was found to be associated with increased total serum cholesterol, and clinical monitoring, including basal lipid levels and periodic follow-up lipid assessments in patients on clozapine, is recommended.
8. Falls:
Clozapine may cause drowsiness, postural hypotension, motor and sensory instability, which may lead to falls that could result in fractures or other injuries. For patients whose own disease, condition or medication may exacerbate these effects, especially in older patients, conduct a risk assessment at the time of initiation of antipsychotic therapy and repeatedly during the patient’s long-term treatment with antipsychotics.
9. Increased mortality in elderly patients with dementia-related psychosis:
The risk of death is increased when atypical antipsychotics are used to treat elderly patients with dementia-associated psychosis. An analysis of 17 placebo-controlled clinical trials (mean plural treatment duration of 10 weeks), mostly in patients treated with atypical antipsychotics, showed that the risk of death was 1.6 to 1.7 times greater in the drug-treated group than in the placebo-controlled group. In a typical 10-week controlled trial, the mortality rate was 4.5% in the drug-treated group and 2.6% in the placebo-controlled group. Although the causes of death varied, most deaths were due to cardiovascular disease (e.g., heart failure, sudden death) or infection (e.g., pneumonia). Observational studies suggest that, similar to atypical antipsychotics, typical antipsychotics may also increase mortality. It is unclear how much of the increased chance of death seen in observational studies is due to the antipsychotic rather than the patient’s somatic disorder. Clozapine is not approved for the treatment of patients with dementia-associated psychosis (see [cautionary statement]).
10. Eosinophilia:
Clozapine-associated eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. This organ involvement may be consistent with a drug response to a syndrome of eosinophilia and systemic symptoms, also known as drug-induced hypersensitivity syndrome (DIHS). If eosinophilia develops during clozapine treatment, prompt evaluation for signs and symptoms of systemic reactions such as rash or other allergic symptoms, myocarditis, or other organ-specific disorders associated with eosinophilia should be performed. If systemic disease associated with clozapine is suspected, clozapine should be discontinued immediately.
If eosinophilia is determined to be due to a cause unrelated to clozapine (e.g., asthma, allergic reactions, parasitic infections, and specific tumors), the disease causing the eosinophilia should be treated and clozapine should be continued. Continue monitoring in the absence of organ involvement. If eosinophil counts continue to increase for several weeks in the absence of systemic disease, management should be based on an overall clinical assessment and in consultation with an internist or hematologist.
11. Prolonged QT interval:
Prolonged QT interval, tip-twist ventricular tachycardia and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have been reported with clozapine therapy. The presence of other risk factors for QT interval prolongation and serious cardiovascular reactions should be considered when using clozapine. Conditions that increase these risks include a history of QT interval prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant arrhythmias, recent myocardial infarction, decompensated heart failure, treatment with other drugs that can cause QT interval prolongation, treatment with drugs that inhibit clozapine metabolism, and electrolyte abnormalities. Prior to treatment with clozapine, a careful physical examination should be performed with a detailed history and history of concomitant medication use. Check electrocardiogram and blood electrolytes.
If the QTc interval exceeds 500 ms, clozapine should be discontinued and managed in consultation with an internist or cardiologist. Perform cardiac evaluation and discontinue clozapine if patient develops symptoms consistent with tip-twist ventricular tachycardia or other symptoms of arrhythmia (e.g., syncope, dizziness, or palpitations).
Use caution with drugs that prolong the QT interval or inhibit clozapine metabolism. Hypokalemia and hypomagnesemia increase the risk of QT interval prolongation. Hypokalemia may result from treatment with diuretics, diarrhea, and other causes. Special care should be taken when treating patients at risk for significant electrolyte disturbances, especially hypokalemia. Electrolytes should be monitored before and periodically during the use of clozapine.
12. Psychotic relapse and cholinergic rebound after abrupt discontinuation:
If abrupt discontinuation of clozapine is required (e.g., due to severe granulocyte deficiency or other medical conditions), careful monitoring should be performed for recurrence of psychotic symptoms and cholinergic rebound symptoms such as profuse sweating, headache, nausea, vomiting, and diarrhea.
13. Cerebrovascular adverse reactions:
In controlled trials, patients with dementia-related psychosis treated with some atypical antipsychotics were at increased risk (including death) of adverse cerebrovascular reactions (e.g., stroke, transient ischemic attack). The mechanism for this increased risk is not known. This increased risk cannot be excluded for clozapine or other antipsychotics, or in other patient populations. Caution should be used in patients with risk factors for cerebrovascular adverse reactions.
General Precautions.
Clozapine has a significant risk of granulocytic deficiency and seizures, and is associated with a high risk throughout the course of treatment, so that prolonged courses of therapy are contraindicated in patients who do not have a significant effect with clozapine. In contrast, patients who have had good results with clozapine and still need to continue taking the drug should be checked and evaluated periodically. Use with caution in patients who have had granulocyte deficiency caused by other drugs.
Fever.
During the application of clozapine therapy, patients may develop a transient fever, with temperatures rising to 38°C, with the highest incidence during the first 3 weeks of treatment. This fever is self-limiting and may be treated with interruption of therapy. It may sometimes be accompanied by an increased or decreased white blood cell count. Patients with fever should be monitored closely to prevent the development of infection or granulocyte deficiency. In addition, hyperthermia should be considered as a possibility of nerve blocker malignant syndrome. There have been many reports of clozapine combined with lithium salts or other drugs with CNS activity resulting in fever due to nerve blocker malignant syndrome.
Pulmonary embolism.
The possibility of pulmonary embolism should be considered in patients taking clozapine who have deep vein thrombosis, acute dyspnea, chest pain, or other respiratory signs and symptoms. Deep vein thrombosis may be observed with clozapine therapy. It is not clear whether pulmonary embolism is caused by clozapine or by the patient’s specific constitution, but the formation of deep vein thrombosis or the presence of respiratory symptoms suggests the development of pulmonary embolism.
Hepatitis.
Serious life-threatening hepatic impairment, including liver failure, hepatic necrosis, and hepatitis, has been reported in post-marketing studies with clozapine. Clozapine should be used with caution in patients with liver disease. Hepatitis has been reported in patients with or without normal liver function prior to drug administration. Liver function should be checked as soon as symptoms of nausea, vomiting and/or anorexia are observed during the use of clozapine. If the test results are consistent with clinical manifestations of hepatitis or the onset of jaundice, discontinue the drug.
Toxicity of anticholinergic effects.
Clozapine has a strong anticholinergic effect and should be used with caution in patients with closed-angle glaucoma and prostatic hypertrophy. Clozapine can cause varying degrees of impairment of intestinal motility, manifested as constipation, intestinal obstruction, fecal impaction and paralytic intestinal obstruction, but is rarely fatal. Treatment of constipation begins with adequate hydration and is supplemented by other treatments, such as the use of laxatives. For severe cases a consultation with a gastrointestinal specialist is possible.
The sedative effect of clozapine when started in patients with cognitive and motor dysfunction can impair psychological and/or physical function, especially during the first days of treatment. It is therefore recommended to gradually and slowly increase the dose and to ensure close monitoring.
Application in patients with co-morbidities.
Clinical experience with the use of clozapine in patients with concomitant other diseases is limited. It should be used with caution in patients with renal or cardiac disease.
In patients undergoing general anesthesia.
Clozapine should be used with caution in patients who are to undergo general anesthesia due to its effects on the central nervous system.
For patients who require surgical procedures, check with the anesthesiologist to discontinue clozapine treatment.
It is not recommended to drive vehicles, operate machinery or work at height during the drug administration.
Pregnant women and nursing mothers
There are no adequate clinical studies in pregnant women. It is contraindicated in pregnant women.
Lactating women should stop breastfeeding during the use of clozapine.
Pediatric Use]
The safety and efficacy of clozapine in children is not known and should not be used in children under 12 years of age.
Geriatric Use]
A sufficient number of elderly patients aged 65 years were not enrolled in clinical studies of clozapine to conclusively determine whether the response of elderly patients differs from that of younger patients.
Postural hypotension and tachycardia can occur with clozapine treatment, with a prevalence of tachycardia of approximately 25% (see warnings under [Precautions] for details). Geriatric patients, especially those with cardiovascular dysfunction, should be aware of these adverse effects.
Elderly patients are more sensitive to the anticholinergic effects of clozapine, such as urinary retention and constipation (see Toxicity of Anticholinergic Effects under [Precautions] for more information).
Dose selection in elderly patients is important and should take into account reduced hepatic, renal or cardiac function, co-morbidities or the combination of other drugs. Other clinical trials have reported the highest incidence of delayed-onset dyskinesia in elderly patients, especially in elderly female patients (see warnings under [Precautions] for more information).
Drug Interactions]
1. The combination of other psychotherapeutic drugs may affect the blood concentration of clozapine, resulting in fluctuations in the blood concentration of clozapine. To avoid adverse reactions and affect clinical efficacy, the dose of clozapine should be adjusted.
2. Although the exact mechanism of granulocyte deficiency caused by clozapine is not clear, various triggering factors may act synergistically with clozapine to increase the risk of bone marrow suppression. Therefore, the combination of clozapine with drugs known to have a suppressive effect on bone marrow (e.g. digoxin, heparin, phenytoin, warfarin) is prohibited.
3. Because of its central nervous system effects, clozapine should be combined with other drugs with central nervous system activity or alcohol with caution.
Postural hypotension in patients taking clozapine is rare (incidence approximately 1/3,000) and is associated with profound hypovolemia, respiratory arrest, and/or cardiac arrest. Some patients taking benzodiazepines have experienced collapse, respiratory arrest, and cardiac arrest at the start of clozapine treatment. Similar episodes have occurred with other antipsychotics or with clozapine alone. The interaction of clozapine with benzodiazepines or other antipsychotics is not known; however, patients taking benzodiazepines or other antipsychotics should take special care when starting clozapine therapy.
5. Clozapine may enhance the antihypertensive effect of antihypertensive drugs and the anticholinergic effect of atropine drugs. Because clozapine may have a reversing adrenergic effect, adrenaline should be avoided in the treatment of clozapine-induced hypotension.
6. Clozapine is a metabolic substrate for several cytochrome P450 isozymes (especially CYP1A2, CYP2D6, and CYP3A4); therefore, the risk of metabolic interactions resulting from effects on the action of one isoenzyme is minimal. However, when clozapine is combined with drugs that are inducers of these enzymes (e.g., phenytoin, nicotine, aminoglutethimide, and rifampin), the blood levels of clozapine can be reduced; and when combined with drugs that are inhibitors of these enzymes (e.g., cimetidine, caffeine, citalopram, ciprofloxacin, fluvoxamine, and erythromycin), adverse effects can be increased. Special care should be taken.
7. The combination of clozapine with fluvoxamine, fluoxetine, paroxetine, sertraline and other antidepressants may increase plasma clozapine and desmethylclozapine levels. Special caution should be exercised.
8. Clozapine and other drugs metabolized by P450
CYP2D6 metabolism, the dose should be reduced. Caution should be exercised when combining with other drugs that are metabolized by this enzyme system isoenzymes such as antidepressants, phenothiazines, aminoglutethimides and typical 1C antiarrhythmics (e.g., propafenone, flecainide and enkephalin) or drugs that inhibit this enzyme (e.g., quinidine).
9. The combination of clozapine with lithium carbonate carries an increased risk of convulsions, neuroblocker malignant syndrome, psychosis and dystonia.
10. The combination of clozapine and macrolide antibiotics can significantly increase plasma clozapine concentration and has been reported to induce seizures.
Drug overdose]
Signs and symptoms of clozapine overdose are generally: altered state of consciousness, including drowsiness, delirium, coma; tachycardia; hypotension; respiratory depression or failure; salivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred rarely. Death by overdose has also been reported, usually at doses above 2500 mg. Of course, there have been reports of patients who have recovered from doses exceeding 4g.
Overdose management: establish and maintain a patent airway; ensure adequate oxygen and ventilation. For the management of drug overdose, the combination of activated charcoal and sorbitol is more effective than emetic or lavage. Examination of the heart and vital organs and general symptoms should be performed in parallel with supportive treatment. In addition, monitoring should be continued over the following days to prevent delayed effects. Epinephrine and its derivatives should be avoided in the treatment of hypotension, and quinidine and proguanil should be avoided in the treatment of cardiac arrhythmias.
There is no specific antidote for clozapine. Forced diuresis, osmotic blood lavage and blood transfusions are also ineffective. For the management of overdose poisoning, physicians recommend the use of multiple drug combinations.
Pharmacology and Toxicology
This product is a dibenzodiazepine antipsychotic. It has strong blocking effects on 5-hydroxytryptamine (5-HT2A) receptors and dopamine (DA1) receptors in the brain, and also has blocking effects on dopamine (DA4) receptors, and weak blocking effects on dopamine (DA2) receptors, in addition to anti-cholinergic (M1), anti-histamine (H1) and anti-alpha-adrenergic receptor effects. It can directly inhibit the brainstem reticular upstream activation system, and has a strong sedative-hypnotic effect.
Pharmacokinetics]
Fast and complete oral absorption, food has no effect on its absorption rate and degree, after absorption, it is rapidly and widely distributed to all tissues, the bioavailability varies widely among individuals, averaging about 50%-60%, with hepatic first pass effect. After oral administration of clozapine tablets 100 mg twice daily, the mean steady-state plasma peak concentration was 319 ng/mL (range: 102-771 ng/mL), the mean time to peak was 2.5 hours (1-6 hours), and the mean steady-state plasma trough concentration was 122 ng/mL (range: 41-343 ng/mL). The mean elimination half-life after single-dose administration of clozapine 75 mg was 8 hours (4 to 12 hours), compared with a mean elimination half-life of 12 hours (4 to 66 hours) after steady-state was reached at 100 mg administered twice daily. Comparative studies of single and multiple dose administration of clozapine showed a significant increase in elimination half-life after multiple doses compared to after a single dose, suggesting possible concentration-dependent pharmacokinetics. However, at steady state, dose-proportional changes in AUC (area under the curve), clozapine peak and trough plasma concentrations were observed after twice-daily dosing of 37.5, 75 and 150 mg. Clozapine has a high tissue binding rate. It is metabolized by the liver and 80% appears as metabolites in the urine and feces, the main metabolites being N-desmethyl clozapine and N-oxide of clozapine. At the same dose and weight, serum drug concentrations are significantly higher in female patients than in male patients. Smoking accelerates the metabolism of this product, and renal clearance and metabolism are significantly reduced in the elderly. Clozapine concentrations may be increased in patients with significantly impaired renal or hepatic function. At regular doses, clozapine blood levels may be higher than expected in individuals with weak metabolism of the cytochrome P450 isoenzyme CYP2D6 (approximately 3-10% of the population). It can be secreted from breast milk and can cross the blood-brain barrier.
Storage
Keep sealed.
Packaging
High density polyethylene bottle for oral solid medication, 100 tablets/bottle.
Expiration date
18 months.
Execution Standard
Approval number】
State Drug Certificate H32022963
Marketing license holder
Drug marketing licensee: Jiangsu Enhua Pharmaceutical Co.
Registered Address: No. 18, Yangshan Road, Xuzhou Economic Development Zone
Manufacturer
Company Name: Jiangsu Enhua Pharmaceutical Co.
Production Address: No. 18, Yang Shan Road, Xuzhou Economic Development Zone
Postcode：221004
Telephone number: 4009002262
Fax number: 0516-87767118
Web address: www.nhwa-group.com