Treatment-Resistant Schizophrenia

FazaClo® (clozapine, USP) 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, FazaClo® (clozapine, USP) 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 Brief Psychiatric Rating Scale (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 seizures, 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

FazaClo® (clozapine, USP) 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 put him/herself at risk for death.

The effectiveness of clozapine in reducing the risk of recurrent suicidal behavior was demonstrated over a two-year treatment period in the InterSePT™ Trial (see Clinical Trial Data under CLINICAL PHARMACOLOGY). Therefore, FazaClo® (clozapine, USP) treatment to reduce the risk of suicidal behavior should be continued for at least two 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.

Treatment-Resistant Schizophrenia

Administration

FazaClo® (clozapine, USP) rapidly disintegrates after placement in the mouth. The tablets may be chewed if desired. The FazaClo® (clozapine, USP) Orally Disintegrating Tablet dispensed in a blister should be left in the unopened blister until time of use. The orally disintegrating tablet should not be pushed through the blister foil. Just prior to use, peel the foil from the blister and gently remove the orally disintegrating tablet. After removing the tablet from either the blister or the bottle, immediately place the tablet in the mouth and allow to disintegrate and swallow with saliva, or chew as desired. No water is needed to take FazaClo® (clozapine, USP).

Upon initiation of FazaClo® (clozapine, USP) therapy, up to a 1-week supply of additional FazaClo® (clozapine, USP) orally disintegrating tablets may be provided to the patient to be held for emergencies (eg, weather, holidays).

Initial Treatment

It is recommended that treatment with FazaClo® (clozapine, USP) begin with a 12.5 mg dose once or twice daily. The dosing should 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' doses were titrated during the first 2 weeks up to a maximum dose of 500 mg/day on a t.i.d. basis. Subsequent dosage increments were then dosed in a total daily dose range of 100-900 mg/day on a t.i.d. basis, 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 300-600 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 seizures 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 FazaClo® (clozapine, USP), but at the lowest level needed to maintain remission. Because of the significant risk associated with the use of FazaClo® (clozapine, USP), patients should be periodically reassessed to determine the need for maintenance treatment.

Discontinuation of Treatment

In the event of planned termination of FazaClo® (clozapine, USP) therapy, gradual reduction in dose is recommended over a 1-2 week period. However, should a patient's medical condition require abrupt discontinuation (eg, 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 FazaClo® (clozapine, USP) (ie, 2 days or more since the last dose), it is recommended that treatment be reinitiated with a 12.5 mg dose 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 FazaClo® (clozapine, USP). (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 FazaClo® (clozapine, USP) 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 the 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 simultaneously 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 two-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 FazaClo® (clozapine, USP) of at least two years is recommended in order to maintain the reduction of risk for suicidal behavior. After two 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 FazaClo® (clozapine, USP) should be continued. Thereafter, the decision to continue treatment with FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) 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.

FazaClo® (clozapine, USP) is available as 12.5, 25, 100, 150, and 200 mg round, yellow, orally disintegrating tablets packaged in bottles. FazaClo® (clozapine, USP) is also available as 25, 100, 150, and 200 mg tablets packaged in blisters.

FazaClo® (clozapine, USP) Orally Disintegrating Tablets

12.5 mg

1/4-inch diameter tablet debossed with “A05” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap............... NDC No. 18860-101-10

25 mg

5/16-inch diameter tablet debossed with “A06” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap.............. NDC No. 18860-102-10

Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistant blisters per card................................................... NDC No. 18860-102-01

100 mg

½-inch diameter tablet debossed with “A08” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap............... NDC No. 18860-104-10

Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistant blisters per card................................................... NDC No. 18860-104-01

150 mg

9/16-inch diameter tablet debossed with “A09” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap............... NDC No. 18860-105-10

Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistant blisters per card................................................... NDC No. 18860-105-01

200 mg

5/8-inch diameter tablet debossed with “A10” on one side.

Bottles of 100: 100 tablets in an HDPE bottle with child-resistant cap................ NDC No.18860-106-10

Cartons of 48 for Institutional Use Only: 8 cards, 6 non child-resistant blisters per card................................................... NDC No. 18860-106-01

Store and Dispense

Store FazaClo® (clozapine, USP) at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). (See USP Controlled Room Temperature.) Protect from moisture.

KEEP OUT OF REACH OF CHILDREN.

FazaClo® (clozapine, USP) tablets must remain in the original package until used by the patient.

Drug dispensing should not ordinarily exceed a weekly supply. If a patient is eligible for WBC count and ANC testing every 2 weeks, then a 2 week supply of FazaClo® (clozapine, USP) can be dispensed. If a patient is eligible for WBC count and ANC testing every 4 weeks, then a 4 week supply of FazaClo® (clozapine, USP) can be dispensed. Dispensing should be contingent upon the WBC count and ANC testing results.

Distributed by : Azur Pharma, Inc., 1818 Market Street, Suite 2350 Philadelphia, PA 19103. Revised December 2010

Last reviewed on RxList: 1/24/2012
This monograph has been modified to include the generic and brand name in many instances.