Treatment-Resistant Schizophrenia: Upon initiation of clozapine therapy, up to a 1-week supply of additional clozapine tablets may be provided to the patient to be held for emergencies (e.g., weather, holidays).<br/>Initial Treatment:: It is recommended that treatment with clozapine begin with one-half of a 25-mg tablet (12.5 mg) once or twice daily and then be continued with daily dosage increments of 25-50 mg/day, if well tolerated, to achieve a target dose of 300-450 mg/day by the end of 2 weeks. Subsequent dosage increments should be made no more than once or twice weekly, in increments not to exceed 100 mg. Cautious titration and a divided dosage schedule are necessary to minimize the risks of hypotension, seizure, and sedation. In the multicenter study that provides primary support for the effectiveness of clozapine in patients resistant to standard drug treatment for schizophrenia, patients were titrated during the first 2 weeks up to a maximum dose of 500 mg/day, on a t.i.d. basis, and were then dosed in a total daily dose range of 100-900 mg/day, on a t.i.d. basis thereafter, with clinical response and adverse effects as guides to correct dosing.<br/>Therapeutic Dose Adjustment:: Daily dosing should continue on a divided basis as an effective and tolerable dose level is sought. While many patients may respond adequately at doses between 300-600 mg/day, it may be necessary to raise the dose to the 600-900 mg/day range to obtain an acceptable response. (Note: In the multicenter study providing the primary support for the superiority of clozapine in treatment-resistant patients, the mean and median clozapine doses were both approximately 600 mg/day.) Because of the possibility of increased adverse reactions at higher doses, particularly seizures, patients should ordinarily be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. Clozapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalized seizures. These symptoms may be likely to occur with rapid dose increase and in patients with pre-existing epilepsy. In this case, the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Dosing should not exceed 900 mg/day. Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided.<br/>Maintenance Treatment:: While the maintenance effectiveness of clozapine in schizophrenia is still under study, the effectiveness of maintenance treatment is well established for many other drugs used to treat schizophrenia. It is recommended that responding patients be continued on clozapine, but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of clozapine, patients should be periodicallyreassessed to determine the need for maintenance treatment.<br/>Discontinuation of Treatment:: In the event of planned termination of clozapine therapy, gradual reduction in dose is recommended over a 1 -2 week period. However, should a patient's medical condition require abrupt discontinuation (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as headache, nausea, vomiting, and diarrhea.<br/>Reinitiation of Treatment in Patients Previously Discontinued:: When restarting patients who have had even a brief interval off clozapine, i.e., 2 days or more since the last dose, it is recommended that treatment be reinitiated with one-half of a 25 mg tablet (12.5 mg) once or twice daily . If that dose is well tolerated, it may be feasible to titrate patients back to a therapeutic dose more quickly than is recommended for initial treatment. However, any patient who has previously experienced respiratory or cardiac arrest with initial dosing, but was then able to be successfully titrated to a therapeutic dose, should be re-titrated with extreme caution after even 24 hours of discontinuation. Certain additional precautions seem prudent when reinitiating treatment. The mechanisms underlying clozapine-induced adverse reactions are unknown. It is conceivable, however, that re-exposure of a patient might enhance the risk of an untoward event's occurrence and increase its severity. Such phenomena, for example, occur when immune mediated mechanisms are responsible. Consequently, during the reinitiation of treatment, additional caution is advised. Patients discontinued for WBC counts below 2000/mmor an ANC below 1000/mmmust not be restarted on clozapine.(See WARNINGS .)<br/>Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder: The dosage and administration recommendations outlined above regarding the use of clozapine in patients with treatment-resistant schizophrenia should also be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior. The InterSePT study demonstrated the efficacy of clozapine in treatment of patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior where the mean daily dose was about 300 mg (range 12.5 to 900 mg). Patients previously treated with other antipsychotics were cross-titrated to clozapine over a one-month interval; the dose of the previous antipsychotic was gradually decreased simultaneous with a gradual increase in clozapine dose over the first month of the study. Patients on depot antipsychotic medication began clozapine after one full dosing interval since the last injection.<br/>Recommendations to Reduce the Risk of Recurrent Suicidal Behavior in Patients Who Otherwise Previously Responded to Treatment of Schizophrenia or Schizoaffective Disorder with Another Antipsychotic Medication:: The results of the InterSePT study demonstrated that, for a 2-year treatment period, the probability of a suicide attempt or a hospitalization due to imminent suicide risk is stable at approximately 24% after one year of treatment with clozapine (Figure 1, Clinical Trial Data Section). A course of treatment with Clozapine of at least 2 years is therefore recommended in order to maintain the reduction of risk for suicidal behavior. After 2 years, it is recommended that the patient's risk of suicidal behavior be assessed. If the physician's assessment indicates that a significant risk for suicidal behavior is still present, treatment with clozapine should be continued. Thereafter, the decision to continue treatment with clozapine should be revisited at regularintervals, based on thorough assessments of the patient's risk for suicidal behavior during treatment. If the physician determines that the patient is no longer at risk for suicidal behavior, treatment with clozapine may be discontinued (see recommendations above regarding discontinuation of treatment) and treatment of the underlying disorder with an antipsychotic medication to which the patient has previously responded may be resumed. ;
Clozapine, an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo [b, e] [1,4] dizaepine. The structural formula isCHCINMol. wt. 326.83Clozapine is available in pale yellow tablets of 25 mg, 50 mg and 100 mg for oral administration. 25 mg, 50 mg and 100 mg Tablets Active Ingredient: clozapine is a yellow, crystalline powder, very slightly soluble in water. Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc.
Pharmacodynamics:<br/>Absorption, Distribution, Metabolism and Excretion: Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75-mg dose was 8 hours (range: 4-12 hours), compared to a mean elimination half-life, after achieving steady-state with 100 mg b.i.d. dosing, of 12 hours (range: 4-66 hours). A comparison of single-dose and multiple-dose administration of clozapine showed that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady-state, linearly dose-proportional changes with respect to AUC (area under the curve), peak and minimum clozapine plasma concentrations were observed after administration of 37.5 mg, 75 mg, and 150 mg b.i.d.<br/>Human Pharmacology: In contrast to more typical antipsychotic drugs, clozapine therapy produces little or no prolactin elevation. As is true of more typical antipsychotic drugs, clinical EEG studies have shown that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop. Patients, on rare occasions, may report an intensification of dream activity during clozapinetherapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.<br/>Clinical Trial Data (Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder Who are Judged to be at Risk of Reexperiencing Suicidal Behavior): The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT���), which was a prospective, randomized, international, parallel-group comparison of clozapine vs. olanzapine in patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for re-experiencing suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment, and the remainder were not. Patients met one of the following criteria: Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200-900 mg/day for clozapine and 5-20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics; 65% with anxiolytics; 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the olanzapine group. The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide, (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized), or (3) worsening of suicidality severity as demonstrated by���much worsening���or���very much worsening���from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB, a group of experts blinded to patient data). A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as���treatment resistant���at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years(range 18-69). Most patients were Caucasian (71%), 15% were Black, 1% were Oriental, and 13% were classified as being of���other���races. Data from this study indicate that clozapine had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with olanzapine. This result should be interpreted only as evidence of the effectiveness of clozapine in delaying time to recurrent suicidal behavior, and not a demonstration of the superior efficacy of clozapine overolanzapine. The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized) was lower for clozapine patients than for olanzapine patients at Week 104: clozapine 24% vs. olanzapine 32%; 95% C.I. of the difference: 2%, 14% (Figure 1).
Clozapine is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, or a history of clozapine-induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, clozapine is contraindicated in severe central nervous system depression or comatose states from any cause. Clozapine should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of clozapine induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.
Clozapine Tablets, USP, 25 mg, yellow colored, round, flat faced beveled edged tablets, with���345' debossed on one side and with a facilitated score on the other side, available as:Bottles of 100 (NDC 57664-345-88) Child resistant Caps.Bottles of 500 (NDC 57664-345-13) Clozapine Tablets, USP, 50 mg, yellow colored, round, flat faced beveled edged tablets, with���241' debossed on one side and with a facilitated score on the other side, available as:Bottles of 100 (NDC 57664-241-88) Child resistant Caps.Bottles of 500 (NDC 57664-241-13) Clozapine Tablets, USP, 100 mg, yellow colored, round, flat faced beveled edged tablets, with���347' debossed on one side and with a facilitated score on the other side, available as:Bottles of 100 (NDC 57664-347-88) Child resistant CapsBottles of 500 (NDC 57664-347-13)<br/>Store and Dispense: Store at controlled room temperature 15-30C (59-86F) (see USP). Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for White Blood Cell (WBC) count and Absolute Neutrophil Count (ANC) testing every 2 weeks, then a two-week supply of clozapine for WBC count and ANC testing every 4 weeks, then a four-week supply of clozapine can be dispensed. Dispensing should be contingent upon the WBC count and ANC test results. * Trademark of Thomson Healthcare Inc. CARACO PHARMACEUTICAL LABORATORIES, LTD. Manufactured by:Caraco Pharmaceutical Laboratories, Ltd. C.S. No.: 5223T091150 Elijah McCoy Drive,Detroit, MI 48202
diseasome-diseases:1025, diseasome-diseases:1032, diseasome-diseases:130, diseasome-diseases:1377, diseasome-diseases:1460, diseasome-diseases:1547, diseasome-diseases:2216, diseasome-diseases:3423, diseasome-diseases:347, diseasome-diseases:3841, diseasome-diseases:3852, diseasome-diseases:54, diseasome-diseases:852, diseasome-diseases:94
Human Experience: The most commonly reported signs and symptoms associated with clozapine overdose are: altered states of consciousness, including drowsiness, delirium and coma; tachycardia; hypotension; respiratory depression or failure; hypersalivation. Aspiration pneumonia and cardiac arrhythmias have also been reported. Seizures have occurred in a minority of reported cases. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.<br/>Management of Overdose: Establish and maintain an airway; ensure adequate oxygenation and ventilation. Activated charcoal, which may be used with sorbitol, may be as or more effective than emesis or lavage, and should be considered in treating overdosage. Cardiac and vital signs monitoring is recommended along with general symptomatic and supportive measures. Additional surveillance should be continued for several days because of the risk of delayed effects. Avoid epinephrine and derivatives when treating hypotension, and quinidine and procainamide when treating cardiac arrhythmia. There are no specific antidotes for clozapine. Forced diuresis, dialysis, hemoperfusion and exchange transfusion are unlikely to be of benefit. In managing overdosage, the physician should consider the possibility of multiple drug involvement. Up-to-date information about the treatment of overdose can often be obtained from a certified Regional Poison Control Center. Telephone numbers of certified Poison Control Centers are listed in the Physicians' Desk Reference'.
Extrapyramidal Symptoms: Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia [See Warnings, Tardive Dyskinesia].<br/>Associated with Discontinuation of Treatment: Sixteen percent of 1,080 patients who received clozapine in pre-marketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to clozapine treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS, primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/granulocytopenia/ agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.<br/>Commonly Observed:<br/>Incidence in Clinical Trials: The following table enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials. These rates are not adjusted for duration of exposure. The following table enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least 1 dose of study medication during their participation in InterSePT, which was an adequate and well-controlled 2-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.<br/>Other Events Observed During the Pre-marketing Evaluation of Clozapine: This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine treatment cannot be determined in the absence of appropriate controls in some of the studies. The table above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with clozapine. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1 %, enumerated byorgan system.<br/>Central Nervous System:: loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability.<br/>Cardiovascular System:: edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nose bleed.<br/>Gastrointestinal System:: abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation.<br/>Urogenital System:: dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection.<br/>Autonomic Nervous System:: numbness, polydipsia, hot flashes, dry throat, and mydriasis.<br/>Integumentary (Skin):: pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria.<br/>Metabolic and Nutritional Disorders:: hypercholesterolemia and hypertriglyceridemia.<br/>Musculoskeletal System:: twitching and joint pain.<br/>Respiratory System:: coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing.<br/>Hemic and Lymphatic System:: anemia and leukocytosis.<br/>Miscellaneous:: chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus.<br/>Post-marketing Clinical Experience: Post-marketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with clozapine not mentioned above that have been received since market introduction and that may have no causal relationship with the drug include the following:<br/>Central Nervous System:: delirium; EEG abnormal; exacerbation of psychosis; myoclonus; overdose; paresthesia; possible mild cataplexy; and status epilepticus.<br/>Cardiovascular System:: atrial or ventricular fibrillation and periorbital edema.<br/>Gastrointestinal System:: acute pancreatitis; dysphagia; fecal impaction; intestinal obstruction/paralytic ileus; and salivary gland swelling.<br/>Hepatobiliary System:: cholestasis; hepatitis; jaundice.<br/>Hepatic System:: cholestasis.<br/>Urogenital System:: acute interstitial nephritis and priapism.<br/>Integumentary (Skin):: hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.<br/>Metabolic and Nutritional Disorders:: hypercholesterolemia and hypertriglyceridemia .<br/>Musculoskeletal System:: myasthenic syndrome and rhabdomyolysis.<br/>Respiratory System:: aspiration and pleural effusion.<br/>Hemic and Lymphatic System:: deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and throm-bocytopenia.<br/>Vision Disorders:: narrow angle glaucoma.<br/>Miscellaneous:: CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss.
Treatment-Resistant Schizophrenia: Clozapine is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, clozapine should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. The effectiveness of clozapine in a treatment-resistant schizophrenic population was demonstrated in a 6-week study comparing clozapine and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean BPRS total score of 61 were demonstrated to be treatment resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of clozapine to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect. Because of the significant risk of agranulocytosis and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically re-evaluated.<br/>Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorders: Clozapine is 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, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that puts him/herself at risk for death. The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT Trial (see Clinical Trial Data under CLINICAL PHARMACOLOGY). Therefore, clozapine treatment to reduce the risk of suicidal behavior should be continued for at least 2 years . The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as anti-depressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.