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

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.

Clozapine-induced myocarditis in children and adolescents: a pharmacovigilance study using VigiBase and a systematic literature review.

INTRODUCTION: Clozapine-induced myocarditis in children (age ≤18 yo) was studied from a PubMed search (18 July 2022) (9 cases) and from the World Health Organization's pharmacovigilance database, called Vigibase, of adverse drug reaction (ADR) reports (72 non-duplicated cases). VigiBase uses a logarithmic measure of disproportionality called the information component (IC). A logistic regression model of presence/absence (40/32) of seriousness in VigiBase was developed. AREAS COVERED: VigiBase provided a significant myocarditis IC = 4.2 with an IC025 = 3.8; only 4 clozapine-induced myocarditis cases were expected, while 72 were observed. The PubMed search identified 9 cases, while VigiBase identified 72 cases (of which 67 did not overlap with published cases). These 76 combined cases included 35 doubtful (most with missing information on the day of diagnosis), 19 possible and 22 probable, according to the ADR scale. After adjusting for confounders, quetiapine increased the risk of seriousness with an odds ratio (OR) of 17.6 (95% confidence interval CI, 1.56 to 198.6), while Australian origin decreased it with an OR = 0.13 (CI, 0.04 to 0.47). EXPERT OPINION: These 41 cases of at least possible clozapine-induced myocarditis indicated that this ADR can definitively occur in children, particularly in the first 30 days of up-titration. Children's and adult cases appeared similar.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries.

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series.

INTRODUCTION: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. METHODS: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. RESULTS: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. CONCLUSIONS: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries / Miocarditis asociada a la clozapina en la base de datos de farmacovigilancia de la Organización Mundial de la Salud: atención a los reportes de los diferentes países

Introduction: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. Methods: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. Results: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005–IC995=5.9–6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. Conclusions: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies. (AU)

Introducción: La incidencia de la miocarditis asociada a clozapina varía en cada país, y esta variación se exploró en VigiBase™, la base de datos de la Organización Mundial de la Salud con más de 25 millones de reportes de reacciones adversas a medicamentos de 145 agencias nacionales de medicamentos. Métodos: El 15 de enero del 2021, se llevó a cabo una búsqueda en VigiBase™ de las miocarditis y clozapina. El componente de información (CI) que es una medida logarítmica de desproporción se usó para estudiar los 3.752 reportes. Con modelos de regresión logística se estudió 3.274 pacientes diferentes después de eliminar los duplicados. Resultados: El primer caso fue publicado en 1980, pero desde 1993 el CI ha sido significativo; ahora es muy alto (CI=6,0; CI005-CI995=5,9-6,1), y estadísticamente significativo de otros antipsicóticos. En los 3.274 pacientes: el 43,4% de los casos fueron no graves, el 51,4% fueron casos graves, pero no letales y el 4,8% fueron casos letales. Australia contribuyó a más de la mitad de los casos (1.621/3.274): con un 69,2% de casos no graves, un 27,7% de casos graves, pero no letales y un 3,1% de casos letales. Cuarenta y un casos fueron de países de Asia. Conclusiones: Los factores de confusión pueden explicar asociaciones estadísticas pero el tamaño y la consistencia de estos resultados son compatibles con que la miocarditis está definitivamente asociada con el tratamiento inicial de la clozapina (el 84% [1.309/1.560] fueron durante el primer mes y otro 5% [82/1.560] durante el segundo). Australia está excesivamente representada, mientras que los países de Asia parecen reportar pocos casos a sus agencias de medicamentos. (AU)

Valproate, obesity and other causes of clozapine poor metabolism in the context of rapid titration may explain clozapine-induced myocarditis: A re-analysis of a Turkish case series / El valproato, la obesidad y otras causas de metabolismo deficiente de la clozapina en el contexto de una titulación rápida de las dosis pueden explicar la miocarditis inducida por clozapina: un nuevo análisis de una serie de casos turca

Introduction: Clozapine-induced myocarditis or any clozapine-induced inflammation may be a hypersensitivity reaction due to titration that was too rapid for the patient's clozapine metabolism. Clozapine metabolism is influenced by ancestry, sex, smoking and the presence of confounders including obesity, infections, and inhibitors (e.g., valproate) causing the patient to behave as a clozapine poor metabolizer (PM). A published study in a Turkish hospital identified 1 case of clozapine-induced pancreatitis and hepatitis and 9 cases of clozapine-induced myocarditis. To explore the hypothesis that the 10 patients were clozapine PMs, their serum clozapine concentrations were investigated using concentration-to-dose (C/D) ratios and their titrations carefully reviewed. Methods: Dividing the trough serum concentration by the dose produces the clozapine C/D ratio. The dose required to reach 350ng/ml was considered the minimum therapeutic dosage and was used to classify patients according to clozapine PM status. Titration speed was assessed. Results: All 10 patients were possibly clozapine PMs (3 of them had as minimum therapeutic doses: 72, 82 or 83mg/day). Nine of the 10 patients may have behaved as clozapine PMs due to obesity and/or valproate co-prescription during titration. One also had an undiagnosed infection. Of the 10 patients, 9 had at least 1 of 3 factors: too-rapid titration in the first or second weeks, or a final dosage that was too high. Conclusions: Future studies using clozapine levels and considering the role of clozapine PM status should explore whether or not all cases of clozapine-induced inflammation could be explained by lack of individualized titration. (AU)

Introducción: Cualquier inflamación inducida por la clozapina, incluida la miocarditis, podría ser una reacción de hipersensibilidad asociada a una titulación demasiado rápida de del fármaco para el metabolismo del paciente. El metabolismo de la clozapina está influenciado por la ascendencia, el sexo, el tabaquismo, y por la presencia de factores de confusión como obesidad, infecciones e inhibidores, como el valproato, que hacen que el paciente se comporte como un metabolizador lento (PM). Un estudio publicado identificó un caso de pancreatitis y hepatitis, y 9 casos de miocarditis inducidos por clozapina. Para explorar la hipótesis de que los 10 pacientes eran PM de clozapina, se investigaron sus concentraciones séricas de clozapina utilizando relaciones concentración/dosis (C/D) y revisando sus titulaciones. Métodos: La dosis necesaria para alcanzar 350ng/ml se consideró la dosis terapéutica mínima y clasificó a los pacientes según el estado de PM de clozapina. Se evaluó la velocidad de titulación. Resultados: Los 10 pacientes eran posiblemente PM de clozapina (3 tenían dosis terapéuticas mínimas: 72, 82 u 83mg/día). Nueve pacientes pueden haberse comportado como PM de clozapina debido a obesidad y/o prescripción conjunta de valproato durante la titulación. Uno también tenía una infección no diagnosticada. Nueve de los 10 pacientes tenían al menos uno de los 3 factores siguientes: titulación demasiado rápida en la primera o segunda semana, o una dosis final excesiva. Conclusiones: Futuros estudios que utilicen niveles de clozapina y consideren el PM deberían explorar si la inflamación inducida por clozapina podría explicarse por la falta de titulaciones individualizadas. (AU)

Association between myocarditis and antipsychotics other than clozapine: a systematic literature review and a pharmacovigilance study using VigiBase.

INTRODUCTION: Pharmacovigilance studies have definitely established that clozapine can cause myocarditis. Two published reviews suggested that on rare occasions other antipsychotics may induce myocarditis. AREAS COVERED: This review explored myocarditis associated with antipsychotics other than clozapine by conducting a systematic search of the literature and critically analyzing the current data in VigiBase compared to the data on clozapine-associated myocarditis. VigiBase is the World Health Organization's global pharmacovigilance database that uses a statistical signal for associations with a logarithmic measure of disproportionality called the information component (IC). EXPERT OPINION: For quetiapine, VigiBase provided 106 reports of myocarditis and a significant statistical signal (IC = 1.8; IC025 = 1.5) which was confounded by 48% (51/106) with clozapine co-prescription. Combining the literature and VigiBase cases provided five probable myocarditis cases during quetiapine monotherapy (4 after overdose or rapid titration). For olanzapine, VigiBase provided 107 reports of myocarditis and a significant statistical signal (IC = 2.1; IC025 = 1.8) probably explained by 77% (82/107) using clozapine co-prescription. Combining the literature and VigiBase cases provided one probable myocarditis case during olanzapine monotherapy. Combining the literature and VigiBase provided another three probable cases during therapy with other antipsychotics during overdose or titration with a high dose.

Should we routinely add CRP to clozapine titrations? - Learning from three cases.

Objectives: An international guideline recently provided certain personalized schedules for titrating clozapine in adult inpatients by considering: 1) DNA ancestry group, 2) sexsmoking subgroup, and 3) presence/absence of clozapine poor metabolizer (PM) status. Measuring CRP levels at baseline and during the first 4 weeks is recommended. Titrations too fast for the metabolism of specific patients can lead to clozapine-induced inflammations and CRP elevations. Methods: Three published cases are reinterpreted. Better outcomes might have been obtained by using the guideline. Results: Case 1 was a Chinese male non-smoker, a clozapine PM due to an underlying inflammation. Case 2 was a Turkish female non-smoker who developed clozapine-induced myocarditis in the context of 4 risk factors (undiagnosed infl ammation, obesity, valproate and olanzapine co-prescription). Case 3 was a United States patient of European ancestry with no known risk factors who developed myocarditis after a routine titration and had an unsuccessful rechallenge with 12.5 mg/day. Application of the international clozapine titration guideline may have prevented: 1) Case 1 by recommending against clozapine titration for a patient with an abnormal CRP level, 2) Case 2 by considering 4 risk factors and using a slow titration for clozapine PMs, and 3) Case 3 by using CRP elevations for early identification of a possible genetic PM. Conclusions: When baseline or prior CRPs are normal and then become abnormal during a clozapine titration, this indicates: 1) clozapine-induced inflammation associated with too-rapid titration for that specific patient, and/or 2) co-occurrence of an infection. Prospective studies need to verify this hypothesis.

Clozapine-associated myocarditis in the World Health Organization's pharmacovigilance database: Focus on reports from various countries.

INTRODUCTION: The incidence of clozapine-associated myocarditis varies by country. These variations were explored in VigiBase, the World Health Organization's global database which has >25 million spontaneously reported adverse drug reaction (ADR) reports from 145 national drug agencies. METHODS: On January 15, 2021, a search of VigiBase since inception focused on myocarditis in clozapine patients. The 3572 individual reports were studied using the standard VigiBase logarithmic measure of disproportionality called information component (IC). The IC measures the disproportionality between the expected and the reported rates. After duplicates were eliminated there were 3274 different patients with myocarditis studied in logistic regression models. RESULTS: The first case was published in 1980 but since 1993 the VigiBase clozapine-myocarditis IC has been significant; moreover, currently it is very strong (IC=6.0, IC005-IC995=5.9-6.1) and statistically significantly different from other antipsychotics. Of the 3274 different patients with myocarditis, 43.4% were non-serious cases, 51.8% were serious but non-fatal, and 4.8% were fatal. More than half (1621/3274) of the reports came from Australia, of which 69.2% were non-serious, 27.7% serious but non-fatal, and 3.1% fatal. Asian countries contributed only 41 cases. CONCLUSIONS: In pharmacovigilance studies, confounding factors may explain statistical associations, but the strength and robustness of these results are compatible with the hypothesis that myocarditis is definitively associated with early clozapine treatment (84% [1309/1560] and 5% [82/1560] in the first and second months). Myocarditis reports from Australia are over-represented to a major degree. Asian countries may be underreporting myocarditis to their drug agencies.

Rapid Extracorporeal Membrane Oxygenation Overcomes Fulminant Myocarditis Induced by 5­Fluorouracil.

Fulminant myocarditis is a rare but potentially life-threatening illness caused by 5-fluorouracil cardiotoxicity. Data supporting the use of extracorporeal membrane oxygenation for the treatment of fulminant myocarditis are limited. A 49-year-old, previously healthy white man, recently diagnosed with anal squamous cell carcinoma, developed severe chest pain hours after completing his first 96-hour intravenous 5-fluorouracil treatment. Over a period of 3 days from onset of symptoms, the patient developed cardiogenic shock secondary to fulminant myocarditis induced by 5-fluorouracil cardiotoxicity. This required emergency initiation of extracorporeal membrane oxygenation. The patient's systolic function recovered by day 5, and on the 17th day he was discharged in hemodynamically stable condition, without symptoms of heart failure. This case shows the importance of prompt recognition of cardiogenic shock secondary to 5-fluorouracil-induced myocarditis and how the immediate initiation of extracorporeal membrane oxygenation can restore adequate tissue perfusion, leading to myocardial recovery and ultimately the survival of the patient.

Clozapine-induced myocarditis may be associated with rapid titration: A case report verified with autopsy.

Clozapine-induced myocarditis is a poorly understood, rare, potentially fatal adverse drug reaction with absolute risks ranging from 7 to 34 per 1000 in Australia and 0.07-0.6 per 1000 in other countries. Hypersensitivity reactions have been postulated including some cases probably associated with rapid titrations. This case describes a 50-year-old African-American man with schizoaffective disorder, naïve to clozapine, who probably died from clozapine-induced myocarditis. He was started on 25 mg/day of clozapine and received 1625 mg over 14 days, prior to his death on day 15. The autopsy found predominantly lymphocytic infiltrate of the perivascular soft tissue and myocardium of the ventricles, with occasional eosinophils. Using the Liverpool ADR Causality Assessment Tool, it was deemed probable that the patient's death was secondary to myocarditis. The patient had fulminant death with no obvious changes in vital signs. Neither C-reactive protein nor troponin was measured, but it is unlikely that the results would have arrived in time to prevent the patient's death. Age, rapid titration, and concomitant use of valproate contributed to this case, which was probably an idiosyncratic adverse drug reaction associated with rapid titration. Lamotrigine-induced Stevens-Johnson syndrome also appears to be an idiosyncratic adverse drug reaction associated with rapid titration, but its incidence has been remarkably reduced since the recommended starting lamotrigine dose was reduced and corrected by the effect of inhibitors such as valproate. Similarly, clozapine-induced myocarditis incidence probably can be reduced with the use of slow titrations, including even slower titrations for patients with lower ability to metabolize clozapine, such as those taking valproate.

Clozapine-induced myocarditis: recognizing a potentially fatal adverse reaction.

A 46-year-old man with a history of paranoid schizophrenia was admitted with a recurrence of psychotic symptoms. Improvement was noted after the initiation of clozapine. After 2 weeks of clozapine therapy, chest pressure and abnormal cardiac biomarkers (in the presence of a normal coronary angiogram) raised suspicion of myocarditis. That diagnosis was confirmed by means of cardiac magnetic resonance imaging. Discontinuation of the clozapine led to resolution of the cardiac symptoms. Clozapine-induced myocarditis is rare and can be missed for lack of specific clinical findings. In order to prevent disease progression and a possibly fatal outcome, early recognition of the condition and prompt discontinuation of clozapine are necessary.

Ventricular fibrillation cardiac arrest due to 5-fluorouracil cardiotoxicity.

The antimetabolite chemotherapeutic agent 5-fluorouracil is used to treat a variety of cancers. Although 5-fluorouracil is generally well tolerated, its toxicity profile includes potential cardiac ischemia, vasospasm, arrhythmia, and direct myocardial injury. These actual or potential toxicities are thought to resolve upon cessation of the medication; however, information about the long-term cardiovascular effects of therapy is not sufficient. We present the case of a 58-year-old man who had 2 ventricular fibrillation cardiac arrests, with evidence of coronary vasospasm and myocarditis, on his 4th day of continuous infusion with 5-fluorouracil. External defibrillation and cessation of the 5-fluorouracil therapy resolved the patient's electrocardiographic abnormalities. In addition to reporting the clinical manifestations of 5-fluorouracil-associated cardiotoxicity in our patient, we discuss management challenges in patients who develop severe 5-fluorouracil-induced ventricular arrhythmias.