Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Leyden Delta BV, Neerbosscheweg 620, 6544 LL, Nijmegen, The Netherlands
Clozapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.
Clozapine is also indicated in psychotic disorders occurring during the course of Parkinson’s disease, in cases where standard treatment has failed.
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.
Initiation of clozapine treatment must be restricted to those patients with a WBC count ≥3500/mm³ (3.5x109/L) and an ANC ≥2000/mm³ (2.0x109/L) within standardised normal limits.
Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacodynamic and pharmacokinetic interactions with clozapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see section 4.5).
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.
The following dosages are recommended.
12.5 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.
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.
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.
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.
In the event of planned termination of clozapine therapy, a gradual reduction in dose over a 1- to 2-week period is recommended. If abrupt discontinuation is necessary, the patient should be carefully observed for the occurrence of withdrawal reactions (see section 4.4).
In patients in whom the interval since the last dose of clozapine exceeds 2 days, treatment should be re-initiated with 12.5 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. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see section 4.4), but was then able to be successfully titrated to a therapeutic dose, re-titration should be carried out with extreme caution.
The starting dose must not exceed 12.5 mg/day, taken in the evening. Subsequent dose increases must be 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.
The mean effective dose is usually between 25 and 37.5 mg/day. In the event that treatment for at least one week with a dose of 50 mg fails to provide a satisfactory therapeutic response, dosage may be cautiously increased by increments of 12.5 mg/week.
The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of 100 mg/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.
When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status. If this approach results in the recurrence of psychotic symptoms, clozapine dosage may be increased by increments of 12.5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see above).
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 (see section 4.4). In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
Patients with hepatic impairment should receive clozapine with caution along with regular monitoring of liver function tests (see section 4.4).
No paediatric studies have been performed. The safety and efficacy of clozapine in children and adolescents under the age of 16 years have not yet been established. It should not be used in this group until further data become available.
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/day.
Zaponex is administered orally. Immediately upon opening the blister or bottle, using dry hands, remove the tablet and place the entire orodispersible tablet on the tongue. Tablet disintegration occurs rapidly in saliva.
In cases of acute intentional or accidental clozapine overdose for which information on the outcome is available, mortality to date is about 12%. Most of the fatalities were associated with cardiac failure or pneumonia caused by aspiration and occurred at doses above 2000 mg. There have been reports of patients recovering from an overdose in excess of 10 000 mg. However, in a few adult individuals, primarily those not previously exposed to clozapine, the ingestion of doses as low as 400 mg led to life-threatening comatose conditions and, in one case, to death. In young children, the intake of 50 to 200 mg resulted in strong sedation or coma without being lethal.
Drowsiness, lethargy, areflexia, coma, confusion, hallucinations, agitation, delirium, extrapyramidal symptoms, hyperreflexia, convulsions; hypersalivation, mydriasis, blurred vision, thermolability; hypotension, collapse, tachycardia, cardiac arrhythmias; aspiration pneumonia, dyspnoea, respiratory depression or failure.
There are no specific antidotes for clozapine.
Gastric lavage and/or administration of activated charcoal within the first 6 hours after the ingestion of the drug. Peritoneal dialysis and haemodialysis are unlikely to be effective. Symptomatic treatment under continuous cardiac monitoring, surveillance of respiration, monitoring of electrolytes and acid-base balance. The use of epinephrine should be avoided in the treatment of hypotension because of the possibility of a ‘reverse epinephrine’ effect.
Close medical supervision is necessary for at least 5 days because of the possibility of delayed reactions.
PVC/PVDC/Al blisters: 2 years.
HDPE containers: 2 years.
PVC/PVDC/Al blisters: This medicinal product does not require any special storage conditions.
HDPE containers: This medicinal product does not require any special storage conditions.
Zaponex 12.5 mg orodispersible tablets are available in either:
PVC/PVDC/Al blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
PVC/PVDC/Al perforated unit-dose blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
HDPE bottles with or without cotton filler with a child-resistant twist-off PP closure for hospital use containing 250 or 500 tablets.
Zaponex 25 mg orodispersible tablets are available in either:
PVC/PVDC/Al blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
PVC/PVDC/Al perforated unit-dose blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
HDPE bottles with or without cotton filler with a child-resistant twist-off PP closure for hospital use containing 250 or 500 tablets.
Zaponex 50 mg orodispersible tablets are available in either:
PVC/PVDC/Al blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
PVC/PVDC/Al perforated unit-dose blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
HDPE bottles with or without cotton filler with a child-resistant twist-off PP closure for hospital use containing 250 or 500 tablets.
Zaponex 100 mg orodispersible tablets are available in either:
PVC/PVDC/Al blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
PVC/PVDC/Al perforated unit-dose blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
HDPE bottles with or without cotton filler with a child-resistant twist-off PP closure for hospital use containing 250 or 500 tablets.
Zaponex 200 mg orodispersible tablets are available in either:
PVC/PVDC/Al blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
PVC/PVDC/Al perforated unit-dose blisters containing 7, 10, 14, 20, 28, 30, 40, 50, 56, 60, 84, 90, 98, 100, 250, 300 or 500 tablets.
HDPE bottles with or without cotton filler with a child-resistant twist-off PP closure for hospital use containing 250 or 275 tablets.
Not all pack sizes may be marketed.
No special requirements.
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