Worldwide Differences in Regulations of Clozapine Use

Clozapine remains the drug of choice for treatment-resistant schizophrenia. As a consequence of its long history and complex pharmacology, we suspected wide variation in the regulations of clozapine use across different countries. The summaries of product characteristics (SPCs) from clozapine manufacturers, as well as local and national guidelines in the following selected countries, were reviewed: China, Denmark, Ireland, Japan, The Netherlands, New Zealand, Romania, the UK and the US. Clozapine is available as tablets in all countries, as an oral suspension in all included countries, with the exception of Japan and Romania, as orally disintegrating tablets in the US and China, and as an injectable in The Netherlands. General practitioner prescribing is only available in The Netherlands, New Zealand, the UK and the US, although with some restrictions in some of the countries. In Ireland and China, clozapine is only dispensed through hospital pharmacies. Hematological monitoring is mandatory in all countries but varies substantially in frequency, e.g. in Denmark hematologic monitoring is mandatory weekly for 18 weeks, followed by monthly monitoring, compared with Japan where blood work is required weekly for 26 weeks, followed by biweekly hematologic monitoring thereafter. In most included countries, with the exception of Denmark, Romania and The Netherlands, the manufacturer provides a mandatory hematological monitoring database, and dispensing of clozapine is not permissible without acceptable white blood count and absolute neutrophil count results. Local guidelines in New Zealand recommend echocardiography and routine troponin during the initial phases of treatment with clozapine. Regulations of clozapine vary widely with regard to rules of prescribing and monitoring. A worldwide update and harmonization of these regulations is recommended.