For significant numbers of black patients the standard neutrophil count thresholds did not permit clozapine use as the thresholds did not take BEN into account. Since 2002, clozapine monitoring services in the UK have used reference ranges 0.5 × 109/l lower for patients with haematologically confirmed BEN and similar adjustments are available in the current US criteria, although with lower permissible minima. But even then significant numbers of black patients will not be eligible even though the low neutrophil counts do not in their case reflect disease. The Duffy–Null polymorphism, which protects against some types of malaria, is predictive of BEN. Adverse effects
Clozapine may cause serious and potentially fatal adverse effects. Clozapine carries five black box warnings, including (1) severe neutropenia (low levels of neutrophils), (2) orthostatic hypotension (low blood pressure upon changing positions), including slow heart rate and fainting, (3) seizures, (4) myocarditis (inflammation of the heart), and (5) risk of death when used in elderly people with dementia-related psychosis. Lowering of the seizure threshold may be dose related. Increasing the dose slowly may decrease the risk for seizures and orthostatic hypotension.Common effects include constipation, bed-wetting, night-time drooling, muscle stiffness, sedation, tremors, orthostatic hypotension, high blood sugar, and weight gain. The risk of developing extrapyramidal symptoms, such as tardive dyskinesia, is below that of typical antipsychotics; this may be due to clozapines anticholinergic effects. Extrapyramidal symptoms may subside somewhat after a person switches from another antipsychotic to clozapine. Sexual problems, like retrograde ejaculation, have been reported while taking clozapine.
However severe agranulocytosis can result in spontaneous infection and death, is a severe decrease in the amount of a specific kind of white blood cell called granulocytes. Clozapine carries a black box warning for drug-induced agranulocytosis. Rapid point-of-care tests may simplify the monitoring for agranulocytosis. Clozapine rechallenge
A clozapine "rechallenge" is when someone that experienced agranulocytosis while taking clozapine starts taking the medication again. In countries in which the neutrophil thresholds are higher than those used in the US a simple approach is, if the lowest ANC had been above the US cut off, to reintroduce clozapine but with the US monitoring regime. This has been demonstrated in a large cohort of patients in a hospital in London in which it was found that of 115 patients who had had clozapine stopped according to the US criteria only 7 would have had clozapine stopped if the US cut offs had been used. Of these 62 were rechallenged, 59 continued to use clozapine without difficulty and only 1 had a fall in neutrophils below the US cut off. Other approaches have included the use of other drugs to support neutrophil counts including lithium or granulocyte colony-stimulating factor (G-CSF). However, if agranulocytosis still occurs during a rechallenge, the alternative options are limited. Cardiac toxicity
Clozapine can rarely cause myocarditis and cardiomyopathy.