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Clozapine (Clozapine) - Indications and Dosage

 
 



INDICATIONS AND USAGE

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. (See WARNINGS.)

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 reevaluated.

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 reexperiencing 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 (see DOSAGE AND ADMINISTRATION).

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 antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.

DOSAGE AND ADMINISTRATION

Treatment-Resistant Schizophrenia

Upon initiation of clozapine therapy, up to a one week supply of additional clozapine tablets may be provided to the patient to be held for emergencies (e.g., weather, holidays).

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 to 50 mg/day, if well-tolerated, to achieve a target dose of 300 to 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 to 900 mg/day, on a t.i.d. basis thereafter, with clinical response and adverse effects as guides to correct dosing.

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 to 600 mg/day, it may be necessary to raise the dose to the 600 to 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 preexisting 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.

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 periodically reassessed to determine the need for maintenance treatment.

Discontinuation of Treatment

In the event of planned termination of clozapine therapy, gradual reduction in dose is recommended over a 1 to 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.

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 (see WARNINGS). 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 retitrated 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 reexposure 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/mm3 or an ANC below 1000/mm3 must not be restarted on clozapine. (See WARNINGS.)

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 mg 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.

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 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 (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.

HOW SUPPLIED

Clozapine Tablets USP, 25 mg and 100 mg are available as follows:

The 25 mg tablets are round, peach, scored tablets with C to the left of the score and 7 to the right of the score on one side of the tablet and M on the other side. They are available as follows:

NDC 0378-0825-01
bottles of 100 tablets

The 100 mg tablets are round, green, scored tablets with C11 above the score and blank below the score on one side of the tablet and M on the other side. They are available as follows:

NDC 0378-0860-01
bottles of 100 tablets

NDC 0378-0860-05
bottles of 500 tablets

Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

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 2-week supply of clozapine can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a 4-week supply of clozapine can be dispensed. Dispensing should be contingent upon the WBC count and ANC test results.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505

REVISED OCTOBER 2008
CLOZ:R11

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