Composition :

  • Each tablet NUZIP® 25 contains Clozapine 25 mg
  • Each tablet NUZIP® 100 contains Clozapine 100 mg


Pharmacology :

The absorption of orally administered Clozapine is 90-95%, neither the rate nor the extent of absorption is influenced by food. Clozapine is subject to moderate first-pass metabolism, resulting in an absolute bioavailability of 50-60%. In steady-state conditions, when given twice daily, peak blood levels occur on an average at 2.1 hours (range : 0,4 – 4,2 hours) and the volume of distribution is 1,6 L/kg. Clozapine is approximately 05% bound to plasma proteins. In elimination is biphasic, with a mean terminal half-life of 12 hours (range: 6-26 hours). After single doses of 75 mg, the mean terminal half-life was 7,9 hours, it increases to 14,2 hours when steady-state conditions were reached by administering daily doses of 75 mg for at least 7 days. Dosage increases from 37,5-75 mg and 150 mg given twice daily were found no result during steady state in linearly dose-proportional increases in the area under the plasma concentration/time curve (AUC) and in the peak and minimum plasma concentrations.

Clozapine is almost completely metabolized before excretion. Of the main metabolites, only the demethyl metabolite was found to be active. Its pharmacological actions resemble those of Clozapine, but are considerably weaker and of short duration. Only trace amounts of unchanged drug are detected in the urine and faeces, approximately 50% of the administered dose being excreted as metabolites in the urine and 30% in the faeces.


Indication :

  • Treatment-resistant schizophrenia:

Clozapine is indicated in patients with treatment-resistant schizophrenia, i.e. patients with schizophrenia who are non-responsive to or intolerant of classic antipsychotics.

  • Non-responsiveness is defined as a lack of satisfactory clinical improvement despite the use of adequate doses at least 2 marketed antipsychotics prescribed for adequate durations.
  • Intolerance is defined as the impossibility of achieving adequate clinical benefit with classic antipsychotics because of serve and untreatable neurological adverse reactions (extrapyramidal side effects or tardive dyskinesia).
  • Risk of recurrent suicidal behavior: 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 re-experiencing suicidal behavior, based on history and recent clinical sate. Suicidal behavior refers to actions by a patient that put him/herself at high risk for death

Dosage :

The dosage must be adjusted individually. For each patient, the lowest effective dose should be used. Initiation of Clozapine treatment must be restricted to those patients with a WBC count ≥ 3500/mm3 (3,5 x 109/L) and ANC ≥ 2000/mm3 (2,0 x 109/L), and within standardized normal limits.

Dose adjustment is indicated in patients who are also receiving medicinal products that have pharmacokinetic interaction with Clozapine, such as benzodiazepines or selective serotonin re-uptake inhibitors (see Interactions with other medicinal products and other forms of interaction).

The following dosages are recommended for oral administration.

  • Treatment-resistant schizophrenia:
  • Starting therapy: 12,5 mg (half of 25 mg tablet) once or twice on the first day, followed by 1-2 25 mg tablets on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25-50 mg in order to achieve a dose level of up to 300 mg/day within 2-3 weeks. Thereafter, if required, the daily dose may be further increased in increments of 50-100 mg at half-weekly or, preferably, weekly intervals.
  • Use in the elderly: It is recommended that treatment is initiated at a particularly low dose (12,5 mg given once on the first day) with subsequent dose increments restricted to 25 mg/day. Caution is indicated in patients receiving drugs interacting with Clozapine such as Benzodiazepines, Fluoxetine or Fluoxamine (see Intercations).
  • Use in children: The safety and efficacy of Clozapine in children have not been established.
  • Therapeutic dose range: In most patients, antipsychotic efficacy can be expected with 300-450 mg/day given in divided doses. Some patients may be treated with lower doses, and some patients may require doses up to 600 mg/day. The total daily dose may be divided unevenly, with the larger portion being taken at bedtime. For maintenance dose, see below.
  • Maximum dose: To obtain full therapeutic benefit, a few patients may require larger dose, in which case judicious increments (i.e. not exceeding 100 mg) are permissible up to 900 mg/day. The possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind.
  • Maitenance dose: After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower dose. Careful downward titration id therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose not exceeding 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 1-2 week period is recommended. If abrupt discontinuation is necessary (e.g. because of leucopenia), the patient should be carefully observed for the recurrence of psychotic symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhea.
  • Re-starting therapy: In patients in whom the interval since the last dose of Clozapine exceeds 2 days, treatment should be re-initiated with 12,5 mg (half a 25 mg tablet) given once or twice on the first day. If this dose well tolerated, it may be feasible to titrate the dose the therapeutic level more quickly than is recommended for the initial treatment. However, in any patient who has previously experienced respiratory or cardiac arrest with initial dosing (see Special warnings and Special precautions for use), but was then able to be successfully titrated to a therapeutic dose, re-titration should be done with extreme caution.
  • 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 dosage of other antipsychotics be reduced or discontinued by gradually tapering it downwards. Based on the clinical circumstances, the prescribing physician should judge wheter or not to discontinue the other antipsychotic therapy before initiating treatment with Clozapine.
  • Reducing the risk of suicidal behavior in schizophrenia and scizoaffective disorder: the dosage and administration recommendations described in the preceding section Indication and method od administration regarding the use of Clozapine in patients with treatment-resistant disorder at risk for recurrent suicidal behavior. A course of treatment with Clozapine of at least 2 years in recommended in order to maintain the reduction of risk for suicidal behavior. It is recommended thet the patients risk of suicidal behavior be reassessed after 2 years of treatment and that, thereafter, the decision to continue treatment with Clozapine be re-visited at regular intervals, based on though assessments of patients risk suicidal behavior during treatment.


Presentation and Registration Number:

NUZIP®  25 Box, 5 strips @ 10 tablets; DKL1030815910A1

NUZIP®  100 Box, 3 strips @ 10 tablets; DKL1030815910B1









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