Apo-Clozapine (clozapine) treatment must be initiated on an in-patient basis or in an out-patient setting where medical supervision is available and vital signs can be monitored for a minimum of 6 to 8 hours after the initial 2 to 3 doses.

When treatment is initiated in out-patients, special caution is advised in patients who are receiving benzodiazepines or other psychotropic drugs as these patients may have an increased risk of circulatory collapse accompanied by respiratory and/or cardiac arrest (see Precautions, Drug Interactions). Extra caution is advised in patients with cardiovascular disease or a history of seizures (see Warnings).

Apo-Clozapine is restricted to patients who have a normal white blood cell (WBC) count and differential cell (DC) count and in whom a WBC count and DC count can be carried out at least weekly for the first 26 weeks of treatment with clozapine and at least at 2-week intervals thereafter . Monitoring must continue for as long as the patient is on the drug, as well as for at least four weeks after discontinuation of treatment.

Apo-Clozapine is available only through a distribution system that requires weekly or every-2-week hematological testing prior to the delivery of the next period's supply of medication (see Indications).

Apotex Inc. will provide the Non-rechallengeable Status/Hematological Status of patients to the requesting approved suppliers* of clozapine within 24 hours of receipt of a written request (see Indications). 

On the first day, clozapine should be given at a 12.5 mg dose (one-half of a 25 mg tablet) once or twice, followed by one or two 25 mg tablets on the second day. If well tolerated, the dosage may be increased in daily increments of 25 to 50 mg, achieving a target dose of 300 to 450 mg/day by the end of 2 weeks. Subsequent dosage increases 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.

When Apo-Clozapine therapy is initiated in a patient undergoing oral neuroleptic therapy, it is generally recommended that the other neuroleptic should first be discontinued by tapering the dosage downwards. Once the neuroleptic is completely discontinued for at least 24 hours, Apo-Clozapine treatment can be started as described above. It is generally recommended that Apo-Clozapine should not be used in combination with other neuroleptics.

In most patients, antipsychotic efficacy can be expected within the therapeutic range of 300-600 mg/day in divided doses. The total daily dose may be divided unevenly, with the larger portion at bedtime.

Since improvement may be gradual, continued therapeutic response can be expected beyond the first month treatment.

Occasionally, patients may require doses higher than 600 mg/day to obtain an acceptable therapeutic response. Because of the possibility of increased adverse reactions (particularly seizures) at daily doses of 600 mg and higher, the decision to treat in the range of 600-900 mg/day must be taken prudently. Patients must be given adequate time to respond to a given dose level before escalation to a higher dose is contemplated. THE MAXIMUM DOSE OF 900 MG/DAY SHOULD NOT BE EXCEEDED.

After achieving maximum therapeutic benefit, many patients can be maintained effectively at lower doses. Careful downward titration is recommended to the level of 150 to 300 mg/day in divided doses. At daily doses not exceeding 200 mg, a single administration in the evening may be appropriate.

In the event of planned termination of Apo-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., severe 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 diarrhoea. 

Re-initiation of Treatment in Patients Previously Discontinued
Apo-Clozapine therapy must not be resumed in:

• Patients who have been discontinued from treatment due to neutropenia (ANC<1.5 x 109/L) or severe leukopenia (WBC <2.0 x 109/L, i.e. Non-rechallengeable Status)

• Patients with clozapine-induced myocarditis

When restarting patients who have had even a brief interval off Apo-Clozapine, i.e., two days or more since the last dose, it is recommended that treatment be re-initiated with 12.5 mg (one half of a 25 mg tablet) once or twice on the first day (see Dosage and Administration for hematological testing conditions). 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.

Certain additional precautions seem prudent when re-initiating treatment. The mechanisms underlying some of the Apo-Clozapine-induced adverse reactions are unknown. It is conceivable 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. Therefore, 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.