Worldwide Differences in Regulations of Clozapine Use

Abstract

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.

Clozapine-Induced Gastrointestinal Hypomotility: A 22-Year Bi-National Pharmacovigilance Study of Serious or Fatal ‘Slow Gut’ Reactions, and Comparison with International Drug Safety Advice

“…This is consistent with other reports of low subjective awareness of objective hypomotility [5, 6, 38] and reinforces our earlier observation that clozapine-treated patients may not recognize or experience constipation in the same way as others due to changes in pain sensitivity or habituation, and thus may be less likely to complain [6, 38]. This decreased sensitivity places the responsibility for actively monitoring and treating CIGH on health professionals; yet the potential severity of CIGH remains poorly recognized amongst mental health staff [8, 15, 17, 39–41]. …”

“…In an Australian audit of 67 long-stay patients taking clozapine, there was a high level of baseline hematological and metabolic monitoring, but no monitoring of bowel function [16]. Of particular concern, clozapine treatment guidelines rarely mention the CIGH spectrum, let alone advise on its management [8, 17]. …”

Use of granulocyte-colony stimulating factor to prevent recurrent clozapine-induced neutropenia on drug rechallenge: A systematic review of the literature and clinical recommendations

“…Given the risk of recurrent neutropenia is most substantial during the first 10 weeks of rechallenge (Dunk et al, 2006), it is recommended that monitoring be undertaken at least twice weekly within this period to facilitate G-CSF dose adjustment or discontinuation of clozapine. Monitoring should be continued weekly until 1 year of follow-up, which is in line with the majority of international guidelines (Nielsen et al, 2016). The epidemiology of recurrent clozapine-induced neutropenia is unclear beyond 1 year and as such the necessity of increased frequency of monitoring beyond this point of time is unknown.…”

Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland

“…A pharmacogenetic test for agranulocytosis with adequate predictive validity is unlikely and would likely present ethical challenges [6, 7]. The risk of agranulocytosis is managed in most developed countries by mandatory blood monitoring for patients on clozapine [8]. In the UK patients taking clozapine must enrol in a clozapine monitoring service where it is obligatory to be monitored weekly for the first 18 weeks of treatment.…”

“…Monitoring systems are in place in the United States and in most European countries but the regulation of clozapine use varies substantially between countries [8]. Some countries, including Iceland, have taken a more flexible stance and not enforced such regulations for clozapine prescriptions in view of the fact that there is no other alternative drug available with similar efficacy for treatment resistant schizophrenia, as well as the practical difficulties of regular monitoring in remote areas.…”