ZAPONEX

Posology The dosage must be adjusted individually. For each patient the lowest effective dose should be used. For doses not realisable/practicable with one strength, other strengths of this medicinal product are available. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure and sedation.

0x109/L) within standardised normal limits. 5). Switching from a previous antipsychotic therapy to clozapine It is generally recommended that 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 the other antipsychotic should first be discontinued by tapering the dosage downwards.

5 mg once or twice on the first day, followed by 25 mg once or twice on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks.

Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals. Therapeutic dose range In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day given in divided doses.

The total daily dose may be divided unevenly, with the larger portion at bedtime. Maximum dose To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (not exceeding 100 mg) are permissible up to 900 mg/day.

However, the possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind. 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 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may be appropriate. Ending therapy In the event of planned termination of clozapine therapy, a gradual reduction in dose over a 1- to 2- week period is recommended.

4). 5 mg given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. 4), but was then able to be successfully titrated to a therapeutic dose, re- titration should be carried out with extreme caution.

Summary of the safety profile For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. 4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson’s disease in cases where standard treatment has failed.

While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse reactions, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.

4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation and hypersalivation. 6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine.

The more common events considered to be causes of discontinuation were leukopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder. Blood and lymphatic system Development of granulocytopenia and agranulocytosis is a risk inherent to clozapine treatment.

Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. 4). Table 3 below summarises the estimated incidence of agranulocytosis for each clozapine treatment period. 8 1 From the UK Clozaril Patient Monitoring Service lifetime registry experience between 1989 and 2001.

2 Person-time is the sum of individual units of time that the patients in the registry were exposed to clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000=100,000), or in 200 patients who were in the registry for 500 weeks (200*500=100,000) before experiencing agranulocytosis.

Agranulocytosis Clozapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring.

The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations. 0x109/L), and - in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks and at least 4-week intervals thereafter.

Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of clozapine. Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination.

3). The treating physician should consider performing a pre-treatment ECG. Prescribing physicians must comply fully with the required safety measures. Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation.

Prescriptions should not be issued for periods longer than the interval between two blood counts. 5x109/L) at any time during clozapine treatment. Patients in whom clozapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to clozapine.

At each consultation, a patient receiving clozapine should be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia.

Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients’ blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.

1. - Patients unable to undergo regular blood tests. - History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). - History of clozapine-induced agranulocytosis.

- Impaired bone marrow function. - Uncontrolled epilepsy. - Alcoholic and other toxic psychoses, drug intoxication, comatose conditions. - Circulatory collapse and/or CNS depression of any cause. g. myocarditis). - Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.

- Paralytic ileus. Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged.