Colonic hypomotility has been shown to occur in up to 80% of people prescribed clozapine when gastrointestinal function is measured objectively using radiopaque markers. Clozapine-induced gastrointestinal hypomotility currently has a higher mortality rate than the better known side effect of agranulocytosis. A Cochrane review found little evidence to help guide decisions about the best treatment for gastrointestinal hypomotility caused by clozapine and other antipsychotic medication. Monitoring bowel function and the preemptive use of laxatives for all clozapine-treated people has been shown to improve colonic transit times and reduce serious sequelae. Hypersalivation
Hypersalivation, or the excessive production of saliva, is one of the most common adverse effects of clozapine (30-80%). The saliva production is especially bothersome at night and first thing in the morning, as the immobility of sleep precludes the normal clearance of saliva by swallowing that occurs throughout the day. While clozapine is a muscarinic antagonist at the M1, M2, M3, and M5 receptors, clozapine is a full agonist at the M4 subset. Because M4 is highly expressed in the salivary gland, its M4 agonist activity is thought to be responsible for hypersalivation. Clozapine-induced hypersalivation is likely a dose-related phenomenon, and tends to be worse when first starting the medication. Besides decreasing the dose or slowing the initial dose titration, other interventions that have shown some benefit include systemically absorbed anticholinergic medications such as hyoscine, diphenhydramine and topical anticholinergic medications like ipratropium bromide. Mild hypersalivation may be managed by sleeping with a towel over the pillow at night.
30% of the clozapine patients responded compared to 4% of the controls, with significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Following this study, the US Food and Drug Administration (FDA) approved its use in 1990. Cautious of this risk, however, the FDA required a black box warning for specific side effects including agranulocytosis, and took the unique step of requiring patients to be registered in a formal system of tracking so that blood count levels could be evaluated on a systematic basis.In December 2002, clozapine was approved in the US for reducing the risk of suicide in people with schizophrenia or schizoaffective  judged to be at chronic risk for suicidal behavior. In 2005, the FDA approved criteria to allow reduced blood monitoring frequency. In 2015, the individual manufacturer Patient Registries were consolidated by request of the FDA into a single shared Patient Registry Called The Clozapine REMS Registry. Despite the demonstrated safety of the new FDA monitoring requirements, which have lower neutrophil levels and do not include total white cell counts, international monitoring has not been standardised. Chemistry
Clozapine is a dibenzodiazepine that is structurally very similar to loxapine (originally deemed a typical antipsychotic). It is slightly soluble in water, soluble in acetone, and highly soluble in chloroform. Its solubility in water is 0.1889 mg/L (25 °C). Its manufacturer, Novartis, claims a solubility of <0.01% in water (<100 mg/L).