Before initiating therapy: Patients should have a baseline white blood cell count (WBC) and absolute neutrophil count (ANC), a medical history and physical examination.
Patients with a history of cardiac illness or abnormal cardiac findings on physical examination should be referred to a specialist for other examinations that include an electrocardiogram (ECG), and the patient treated only if expected benefits clearly outweigh the risks.
General Dosing Recommendations: Clozapine may be taken with or without food.
Dosage of clozapine should be carefully adjusted according to individual requirements and response using the lowest effective dosage.
Cautious dosage titration and administration of clozapine in divided doses are necessary to minimize the risk of hypotension, seizures, and sedation.
Initiation of clozapine treatment must be restricted to those patients with a WBC count ≥3500/mm3 (3.5x109/L) and an ANC ≥2000/mm3 (2.0 x 109/L), and within standardized normal limits.
Dose adjustment is indicated in patients who are also receiving drugs that have pharmacodynamic and pharmacokinetic interactions with clozapine (e.g., benzodiazepines or selective serotonin reuptake inhibitors).
Treatment-Resistant Schizophrenia: Starting Dose: 12.5 mg (half of a 25 mg tablet) once or twice a day on the first day and then continued with daily dosage increments of 25 to 50 mg per day, if well tolerated, to achieve a target dose of 300 to 450 mg per day by the end of two weeks.
Subsequent dosage increments should be made no more than once or twice a week, in increments not to exceed 100 mg.
Therapeutic Dose Range: 300 to 450mg per day given in divided doses; The total daily dose may be divided unevenly, with the larger portion at bedtime.
Maximum Dose: 900 mg per day; To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (i.e., not exceeding 100 mg) are permissible up to 900 mg per day. The possibility of increased adverse reactions, particularly seizures, occurring at doses over 450 mg per day must be considered.
Maintenance Dose: After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses. Careful downward titration is therefore recommended. Treatment should be maintained for at least six months. If the daily dose does not exceed 200 mg, once a day administration in the evening may be appropriate. Patients should be periodically reassessed to determine the need for maintenance treatment because of the significant risk associated with clozapine.
Discontinuation of Therapy: Discontinuation of clozapine therapy should be done with a gradual dose reduction over a 1- to 2- week period.
If abrupt discontinuation is required (e.g., leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound (e.g., profuse sweating, headache, nausea, vomiting, and diarrhea).
Reinitiation of Treatment in Patients Previously Discontinued: When reinitiating treatment in patients who have had even a brief interval off clozapine, i.e., two days or more since the last dose, it is recommended that treatment be reinitiated with 12.5 mg (half of a 25 mg tablet) once or twice a day. If this dose is well tolerated, 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 retitrated with extreme caution even after 24 hours of discontinuation. The reexposure of a patient might enhance the risk of occurrence of an untoward event and increase its severity. Such phenomena occur when immune-mediated mechanisms are responsible. Therefore, during the reinitiation of treatment, additional caution is advised.
Patients discontinued for WBC counts below 2,000/mm3 or an ANC below 1,000/mm3 must not be restarted on clozapine.
Switching From a Previous Antipsychotic Therapy to Clozapine: Clozapine should not be used in combination with other antipsychotics. When clozapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that typical antipsychotic should first be discontinued by tapering the dosage downwards. Based on the clinical circumstances, the physician should judge whether or not to discontinue the other antipsychotic therapy before initiating treatment with clozapine.
Reducing the Risk of Recurrent Suicidal Behavior in Patients with Schizophrenia or Schizoaffective Disorder: The dosage and administration recommended to patients with treatment-resistant schizophrenia should be followed when treating patients with schizophrenia or schizoaffective disorder at risk for recurrent suicidal behavior. In order to maintain the reduction of risk for suicidal behavior, a course of treatment with clozapine of at least two years is recommended. After two years, the patient's risk of suicidal behavior should be assessed. If the physician's assessment indicates that a significant risk for suicidal behavior is still present, treatment with clozapine should be continued. Then, the decision to continue treatment with clozapine should be revisited at regular intervals, 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 and treatment of the underlying disorder with an antipsychotic drug to which the patient has previously responded may be resumed.
Psychotic Disorders Occurring During the Course of Parkinson's Disease, In Cases Where Standard Treatment has Failed: Starting Dose: 12.5 mg (half of a 25 mg tablet), taken in the evening.
Subsequent dose increases must be made by 12.5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.
Mean Effective Dose: 25 to 37.5 mg per day.
Dosage may be cautiously increased by increments of 12.5 mg per week, in cases when the treatment for at least one week with a dose of 50 mg fails to provide a satisfactory therapeutic response.
The dose of 50 mg per day should only be exceeded in exceptional cases, and the maximum dose of 100 mg per day must never be exceeded.
Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs. Blood pressure should be monitored during the first weeks of treatment.
In cases of complete remission of psychotic symptoms for at least two weeks, an increase in anti-parkinsonian drug is possible if indicated on the basis of motor status. If this results in the recurrence of psychotic symptoms, clozapine dosage may be increased by increments of 12.5 mg per week up to a maximum of 100 mg per day, taken in one or two divided doses.
Ending therapy: A gradual reduction in dose by steps of 12.5 mg over a period of at least one week (preferably two) is recommended.
Treatment must be discontinued immediately in the event of neutropenia or agranulocytosis. In this case, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
Special Population: In patients with a history of seizures or suffering from renal or cardiovascular disorders: Initial dose: 12.5 mg given once on the first day, and dosage increase should be slow and in small increments.
Geriatric: Initiation of treatment is recommended at a particularly low dose (12.5 mg given once on the first day), with subsequent dose increments restricted to 25 mg per day.
Or, as prescribed by a physician.