Although clozapine is well absorbed from the gastrointestinal tract, its bioavailability is limited to about 50% by first-pass metabolism. Peak plasma concentrations are achieved, on average, about 2.5 hours after oral doses. Clozapine is about 95% bound to plasma proteins and has a mean terminal elimination half-life of about 12 hours at steady state. It is almost completely metabolised and routes of metabolism include N-demethylation, hydroxylation, and Af-oxidation the desmethyl metabolite (norclozapine) has limited activity. The metabolism of clozapine is mediated mainly by the cytochrome P450 isoenzyme CYP1A2. Metabolites and trace amounts of unchanged drug are excreted mainly in the urine and also in the faeces. There is wide interindividual variation in plasma concentrations of clozapine and no simple correlation has been found between plasma concentrations and therapeutic effect. It is distributed into breast milk.
Bioavailability. Mean plasma concentration of clozapine increased from 329 to 629 nanograms/mL in 10 patients when switched from an extemporaneous liquid formulation to conventional tablets.
Uses and Administration
Clozapine is a dibenzodiazepine derivative and the prototype of the atypical antipsychotics. It has relatively weak dopamine receptor-blocking activity at D1, D2, D3, and D5 receptors but has a high affinity for the D4 receptor. Clozapine possesses alpha-adrenergic blocking, antimuscarinic, antihistaminic, antiserotonergic, and sedative properties.
Clozapine is used for the management of schizophrenia however, because of the risk of agranulocytosis, it is reserved for patients who fail to respond to other antipsychotics, including other atypicals, or who experience severe neurological effects with such drugs. In the USA, it may also be used for reducing the risk of recurrent suicidal behaviour in those with schizophrenia or schizoaffective disorder who are at chronic risk for suicidal behaviour. In the UK, it is also used in the management of treatment-resistant psychoses associated with Parkinson’s disease.
Clozapine use must be accompanied by strict procedures for the monitoring of white blood cell counts (see Precautions, above). To minimise the incidence of adverse effects, clozapine therapy should be introduced gradually, beginning with low doses and increasing according to response.
In the treatment of schizophrenia, including reducing the risk of suicidal behaviour, the usual oral dose is 12.5 mg once or twice on the first day followed by 25 mg once or twice on the second day. Thereafter the daily dosage may be increased gradually in steps of 25 to 50 mg to achieve a daily dose of up to 300 mg within 14 to 21 days (in the USA, up to 450 mg daily is permitted by the end of 2 weeks). Subsequent increases in steps of 50 to 100 mg may be made once or twice weekly a daily dosage of 900 mg should not be exceeded. Once a therapeutic response has been obtained, a gradual reduction of dosage to a suitable maintenance dose is recommended most patients respond to 200 to 450 mg daily. The total daily dose is given in divided doses a larger portion may be given at night. Daily maintenance doses of 200 mg or less may be given as a single dose in the evening. If clozapine is to be withdrawn, this should be done gradually over a 1- to 2-week period. However, immediate withdrawal with careful observation is essential if neutropenia develops or if myocarditis or cardiomyopathy is suspected (see Precautions, above).
Elderly patients may require lower doses of clozapine and it is recommended that treatment should start with a dose of 12.5 mg on the first day and that subsequent dose increments should be restricted to 25 mg. For patients who are restarting treatment after an interval of more than 2 days, 12.5 mg may be given once or twice on the first day. If this dose is well tolerated it may be possible to increase the dosage more quickly than when first starting. However, patients who have had respiratory or cardiac arrest with initial dosing, but were then successfully titrated to a therapeutic dose, should be re-titrated with extreme caution after a break of even 24 hours. Additional monitoring of blood cell counts may also be required if treatment is interrupted, see Treatment Break, under Monitoring, above. It is recommended that oral therapy with other antipsychotics should be withdrawn gradually before treatment with clozapine is started. Clozapine has also been given by intramuscular injection.
In the management of treatment-resistant psychoses in Parkinson’s disease, the initial oral dose of clozapine is no more than 12.5 mg once daily in the evening. Thereafter, the daily dosage may be increased in increments of 12.5 mg up to twice a week a dose of 50 mg daily should not be reached before the end of the second week. The usual dose ranges from 25 to 37.5 mg daily. Increases in the daily dose above 50 mg should only be made in exceptional cases in increments of 12.5 mg at weekly intervals up to a maximum of 100 mg daily. The total daily dose should preferably be given as a single dose in the evening. Dosage of anti-parkinsonian drugs may be increased when there has been complete remission of psychotic symptoms after at least 2 weeks of clozapine therapy. If psychotic symptoms recur after increases in antiparkinsonian therapy, the dose of clozapine may need to be increased in line with the above guidance. As in patients with schizophrenia, planned withdrawal of clozapine in patients with Parkinson’s disease should also be gradual in decrements of 12.5 mg over 1 to 2 weeks.
Action. Antipsychotics are thought to work through inhibition of dopamine D2-receptors, but this hypothesis fails to explain the activity of the atypical antipsychotics such as clozapine. How clozapine produces its antipsychotic activity is not clear it has a high affinity for a number of different receptors.
Administration. There has been controversy over the bioequivalence or otherwise of different brands of clozapine. Although some reports indicate that it is perfectly possible to switch from branded to generic clozapine, the need for monitoring and concerns about any requirement for retitration of doses (because of potential lack of bioequivalence) have to be taken into account. There have been a few reports of exacerbation of psychotic symptoms in patients who were switched to a generic formulation.’
Bipolar disorder. Clozapine is of benefit for the treatment of mania in patients with bipolar disorder, and the use of atypical antipsychotics in the management of such patients is increasing. However, the adverse effects of clozapine may restrict its use.
Dementia. Although atypical antipsychotics such as clozapine have been tried in elderly patients with dementia, the licensing authorities in the USA now recommend against such use, see under Precautions, above. For further discussion of the management of disturbed behaviour.
Parkinsonism. Clozapine is used as an alternative to classical antipsychotics in the management of treatment-resistant psychoses in patients with Parkinson’s disease. Some neurologists even consider clozapine to be the antipsychotic of choice in these patients, although this remains to be determined. A review in 1994 considered that there was little evidence to support clozapine as first choice given the quality of the available studies and the need for extensive monitoring. However a subsequent double-blind, placebo-controlled study showed that low-dose clozapine treatment (up to 50 mg daily) significantly improved drug-induced psychosis without worsening parkinsonism. Adverse effects noted in this study were generally mild, although in the clozapine group of 30 patients, there was 1 report of leucopenia. A similar study also reported benefit, although 7 of 32 patients noted some aggravation of parkinsonism, usually mild and transient, while receiving clozapine. Adverse effects reported from other individuals have also included a patient with parkinsonism who had worsening of psychotic symptoms when her dose of clozapine was increased, and the sudden return of psychosis in another patient with parkinsonism whose psychosis was successfully treated with clozapine for 5 years. Low-dose clozapine (about 40 mg daily) also appears to be of benefit in the management of levodopa-induced dyskinesias in patients with severe Parkinson’s disease.
Schizophrenia. Clozapine is an effective antipsychotic for the management of schizophrenia but its use is limited by its blood toxicity. Its effectiveness and superiority over classical antipsychotics was shown in a multicentre study. Patients refractory to at least 3 different antipsychotics and who failed to improve after a single-blind trial of haloperidol, were randomised, double-blind, to treatment for 6 weeks with either clozapine up to 900 mg daily, or chlorpromazine hydrochloride up to 1800mg daily with benzatropine mesilate up to 6 mg daily. Of the 267 patients included in the evaluation, 5 of 141 (4%) improved with chlorpromazine and benzatropine, and 38 of 126 (30%) improved with clozapine. Clozapine was superior to chlorpromazine in the treatment of negative as well as positive symptoms. Reviews’ of clozapine indicate that these findings have been well replicated both in subsequent studies and in clinical practice. It is, however, unclear for how long clozapine should be tried: although 1 study identified new responses up to 12 months after starting therapy, others have indicated that if improvement was not seen within the first 6 to 24 weeks, it was unlikely to occur.
Clozapine is also used to reduce suicide risk in patients with refractory chronic schizophrenia. The reported suicide rate of 0.05% peryear in 6300 patients in the UK given clozapine since 1990 was considered to be tenfold less than expected. A subsequent study found it to be more effective than olanzapine in preventing suicide attempts in patients with schizophrenia or schizoaffective disorder at high risk.
Clozapine has shown consistent clinical benefit in schizophrenic patients with persistent aggressive or violent behaviour. Whether this is due to a sedative effect, a specific antiaggressive action, or just reflects an overall improvement in psychosis is unknown.
Clozapine has been advocated for use in schizophrenic patients with moderate to severe tardive dyskinesia. It is still unclear whether clozapine can itself cause tardive dyskinesia but some patients with established tardive dyskinesia have experienced improvement in their symptoms when using clozapine.’
The United States Pharmacopeia 31, 2008: Clozapine Tablets.
Argentina: Lapenax Sequax
Australia:: Clopine Clozaril
Austria: Lanolept Leponex
Brazil: Leponex Zolapin
Czech Republic: Leponex
Finland: Froidir Leponex
Germany: Elcrit Leponex
Hong Kong: Clozaril
India: Lozapin Sizopin
Indonesia: Clozaril Sizoril
Israel: Leponex Lozapine
Malaysia: Clozaril Zapine
Mexico: Clopsine Leponex
The Netherlands: Leponex
New Zealand: Clopine Clozaril
Poland: Klozapol Leponex
Portugal: Leponex Ozapim
South Africa: Cloment Leponex
Switzerland: Clopin Leponex
Thailand: Cloril Clozaril
UK: Clozaril Denzapine Zaponex
USA: Clozaril FazaClo Fazalco