According to the WHO clozapine pharmacovigilance database, the United Kingdom accounts for 968 fatal outcomes versus 892 in the rest of the world

Leon, José de

doi:10.1111/bcp.15522

Cited by 10 publications

(13 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After-marketing reports of ADRs during the period called post-marketing surveillance 65 led to the development of a new science called pharmacoepidemiology, which includes the concept of pharmacovigilance. 66 Supplementary Table 4 (in the online-only Data Supplement) [66][67][68] explains that pharmacovigilance considers the published reports of ADRs and the reports of the national drug agencies which are sent to the World Health Organization' s pharmacovigilance database called VigiBase. 67 The first pharmacovigilance finding of clozapine-induced agranulocytosis 4 led to the cessation of US clozapine studies that had been started in 1974.…”

Section: Advances In Pharmacovigilance Science Very Slowly Impacted T...mentioning

confidence: 99%

“…Clozapine was the third most lethal drug in the world overall, but was the most lethal drug among nongeriatric adults worldwide. The distribution was uneven since UK physicians reported 968 fatal outcomes versus 892 in the rest of the world (a country with 67 million people had more fatal outcomes in clozapine patients than the entire rest of the world), including only 105 fatal outcomes reported by physicians in the other European countries 68 The major ADRs associated with worldwide fatal outcomes in VigiBase until 2019 have been described 168 and necessarily include these 986 fatal outcomes reported by UK physicians. After the generalized use of weekly hematological monitoring and during 2000-2019, 72 the four major causes of worldwide fatal outcomes in order were: pneumonia with 1,922 (29.5%, 1,922/6,506), sudden deaths/cardiac arrest with 1,221 (90.5%, 1,221/1,349), myocarditis with 484 (11.1%, 484/4,356) and agranulocytosis with 433 (1.5%, 433/29,586).…”

Section: High Lethality In Uk Clozapine Patients Is Puzzlingmentioning

confidence: 99%

“…Based on what we know from VigiBase and UK studies (Supplementary Table 13 in the online-only Data Supplement), it is possible to speculate that pneumonia and sudden death may be the major causes of death among clozapine patients in the UK. 68 The extremely high number of fatal outcomes reported by UK physicians to their drug agency and then to VigiBase appeared hard to believe to the author; unfortunately, a later independent verification indicates the problem is even worse. In an article focused on CIGH, Handley et al 165 found 4,547 UK fatal outcomes from reports of physicians and nonphysicians from 1992 to 2017.…”

Section: High Lethality In Uk Clozapine Patients Is Puzzlingmentioning

confidence: 99%

“…The comparison of transnational fatal outcomes in VigiBase is limited by lack of knowledge of: 68 • ADRs occurring versus those reported,…”

Section: Supplementary Table 1 the Need For An Open-minded Readermentioning

confidence: 99%

See 3 more Smart Citations

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

León

2023

Psychiatry Investig

View full text Add to dashboard Cite

This review article argues against trusting standard clozapine references, including the US package insert, because they do not include advances in the sciences of pharmacokinetics and pharmacovigilance and ignore the effects of ethnic ancestry on therapeutic dosing. The minimum therapeutic dose leading to the minimum therapeutic concentration of 350 ng/mL in serum/plasma can be used to compare individuals/groups with treatment-resistant schizophrenia. The US clozapine package insert recommends targeting doses of 300-450 mg/day and, subsequently, increments of up to 100 mg with a maximum dose of 900 mg/day. Ethnic ancestry is defined by DNA ancestry group. Asians (people with ancestry ranging from Pakistan to Japan) and Indigenous Americans are similar in clozapine dosing; their average clozapine minimum therapeutic dose ranged from 166 mg/day (female non-smokers) to 270 mg/day (male smokers). For those with European ancestry, average clozapine minimum therapeutic doses ranged from 236 mg/day (female non-smokers) to 368 mg/day (male smokers). Based on limited studies, Black (African sub-Saharan ancestry) patients may be treated with typical US doses (300-600 mg/day), assuming no poor metabolism (PM) status. Ancestry's impact on clozapine lethality in four countries is discussed (two countries with highly homogenous populations, Denmark and Japan, and two countries with increasingly heterogenous populations due to immigration, Australia and the UK). An international guideline with 104 authors from 50 countries/regions was recently published, providing 6 personalized clozapine titration schedules for adult inpatients (3 ancestry groups and PM/non-PM schedules) and recommending c-reactive protein monitoring at baseline and weekly for 4 weeks.

show abstract

Section: Advances In Pharmacovigilance Science Very Slowly Impacted T...mentioning

confidence: 99%

Section: High Lethality In Uk Clozapine Patients Is Puzzlingmentioning

confidence: 99%

Section: High Lethality In Uk Clozapine Patients Is Puzzlingmentioning

confidence: 99%

“…The comparison of transnational fatal outcomes in VigiBase is limited by lack of knowledge of: 68 • ADRs occurring versus those reported,…”

Section: Supplementary Table 1 the Need For An Open-minded Readermentioning

confidence: 99%

See 2 more Smart Citations

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

León

2023

Psychiatry Investig

View full text Add to dashboard Cite

show abstract

“…Whereas Leung et al 4 offered a perspective focused on the United States, this article offers the perspective of an international group of collaborators that focuses on worldwide outcomes of clozapine that may be disproportionate and influenced by differing frequencies of clozapine ADRs. We briefly summarize (1) clozapine outcomes in Scandinavian national registries [7][8][9][10][11][12] and (2) clozapineassociated fatal outcomes according to recent pharmacovigilance studies [13][14][15][16][17][18] suggesting that outcomes may vary across countries based on current use. The discussion elaborates on (1) the relatively low contribution of agranulocytosis to current clozapine-associated lethality, (2) pneumonia as the leading cause of death worldwide in clozapine-treated patients, and (3) myocarditis as possibly the second leading cause worldwide, although it may be the top cause in some countries.…”

mentioning

confidence: 99%

Escaping the Long Shadow Cast by Agranulocytosis

Leon

Arrojo-Romero

Verdoux

et al. 2023

J Clin Psychopharmacol

Self Cite

View full text Add to dashboard Cite

Purpose/BackgroundA recent article in this journal presented a US perspective regarding the modernization of clozapine prescription and proposed an escape from the long shadow cast by agranulocytosis.MethodsHere, an international group of collaborators discusses a point of view complementary to the US view by focusing on worldwide outcomes of clozapine usage that may be uneven in terms of frequency of clozapine adverse drug reactions.Findings/ResultsStudies from the Scandinavian national registries (Finland and Denmark) did not find increased mortality in clozapine patients or any clear evidence of the alleged toxicity of clozapine. Data on clozapine-associated fatal outcomes were obtained from 2 recently published pharmacovigilance studies and from the UK pharmacovigilance database. A pharmacovigilance study focused on physician reports to assess worldwide lethality of drugs from 2010 to 2019 found 968 clozapine-associated fatal outcomes in the United Kingdom. Moreover, the United Kingdom accounted for 55% (968 of 1761) of worldwide and 90% (968 of 1073) of European fatal clozapine-associated outcomes. In a pharmacovigilance study from the UK database (from 2008 to 2017), clozapine was associated with 383 fatal outcomes/year including all reports from physicians and nonphysicians. From 2018 to 2021, UK clozapine-associated fatal outcomes increased to 440/year.Implications/ConclusionsThe interpretation of fatal outcomes in each country using pharmacovigilance databases is limited and only allows gross comparisons; even with those limitations, the UK data seem concerning. Pneumonia and myocarditis may be more important than agranulocytosis in explaining the uneven distribution of fatal outcomes in clozapine patients across countries.

show abstract

Adverse drug reactions and their fatal outcomes in clozapine patients in VigiBase: Comparing the top four reporting countries (US, UK, Canada and Australia)

Cuevas

Sanz

Leon

2023

Schizophrenia Research

View full text Add to dashboard Cite

According to the WHO clozapine pharmacovigilance database, the United Kingdom accounts for 968 fatal outcomes versus 892 in the rest of the world

Cited by 10 publications

References 12 publications

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

Reflections on the Lack of Consideration of Ethnic Ancestry to Stratify Clozapine Dosing

Escaping the Long Shadow Cast by Agranulocytosis

Adverse drug reactions and their fatal outcomes in clozapine patients in VigiBase: Comparing the top four reporting countries (US, UK, Canada and Australia)

Contact Info

Product

Resources

About