Pharmacovigilance findings and box warnings in the clozapine package inserts have marked the history of clozapine.
This is the largest review of clozapine adverse drug reactions (ADRs) and their ...associated fatal outcomes. Reports to the World Health Organization's global pharmacovigilance database, VigiBase™, were analyzed, extending from clozapine's introduction to December 31, 2022.
The analysis focused on the top four reporting countries: United States (US), United Kingdom (UK), Canada and Australia (83 % of fatal outcomes worldwide). Attempts were made to control for population and clozapine prescription in each country.
Clozapine ADRs worldwide accounted for 191,557 reports, with the highest number (53,505) in “blood and lymphatic system disorder”. Of the 22,596 fatal outcomes reported in clozapine patients, 9587 were from the US, 6567 from the UK, 3623 from Canada and 1484 from Australia. The top category worldwide in fatal outcomes was nonspecifically labeled “death” with 46 % (range 22–62 %). “Pneumonia” was second with 30 % (range 17–45 %). Agranulocytosis was numerically only the 35th top clozapine ADR associated with fatal outcomes. On average, 2.3 clozapine ADRs were reported per fatal outcome. Infections were associated with 24.2 % of the UK fatal outcomes (9.4 %–11.9 % in the 3 other countries).
The four countries appeared to report clozapine ADRs in different ways, making comparisons difficult. We estimated higher fatal outcomes in the UK and Canada after controlling for cross-sectional estimations of population and published clozapine use. This last hypothesis is limited by the lack of precise estimation of accumulated clozapine use in each country.
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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.
VigiBase provided a significant myocarditis IC = 4.2 with an IC
= 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).
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.
The literature has paid very little attention to pericarditis, pericardial effusion and pancreatitis during clozapine treatment in children and adolescents.
Cases of clozapine-associated pericarditis ...and pancreatitis in children were studied using searches in: 1) PubMed (June 16, 2023), and 2) the World Health Organization's pharmacovigilance database (June 1, 2022), VigiBase. VigiBase uses a logarithmic measure of disproportionality called the information component (IC).
The PubMed search yielded 3 clozapine-associated pericarditis cases, 1 pancreatitis case and 1 with both. VigiBase provided a significant clozapine-associated pericarditis IC = 3.6 with an IC025 = 2.9 (only 3 cases were expected while 22 were observed). VigiBase provided a significant clozapine-associated pancreatitis IC = 2.2 with an IC025 = 1.4 (only 3 cases were expected while 16 were observed). In VigiBase clozapine-associated pericarditis and pericardial effusion in youth looked similar and on a continuum with myocarditis, as myocarditis, pericarditis and pancreatitis appeared to occur mainly during clozapine titration. Combining PubMed and VigiBase we identified: 1) 29 cases of at least possible clozapine-associated pericarditis/pericardial effusion (6 probable and 23 possible) including 7 cases with and 22 without myocarditis, and 2) 17 cases of clozapine-associated pancreatitis (1 definite and 16 possible). Two of the pancreatitis cases occurred during overdoses. No fatal outcomes were found in any clozapine-associated pericarditis and pancreatitis cases.
Despite the lack of attention in the literature to clozapine-associated pericarditis and pancreatitis, results demonstrate that they can happen in youth, particularly during titration. Pericarditis and pancreatitis appear to be forms of clozapine-associated inflammation during dose titration.
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Pharmacovigilance studies have definitely established that clozapine can cause myocarditis. Two published reviews suggested that on rare occasions other antipsychotics may induce myocarditis.
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).
For quetiapine, VigiBase provided 106 reports of myocarditis and a significant statistical signal (IC = 1.8; IC
= 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; IC
= 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.
Since the introduction of omeprazole in 1989, proton pump inhibitors (PPIs) have become the mainstream of treatment for acid-related pathologies, but nowadays, it is estimated that between 20% and ...80% of people worldwide who are using PPIs are doing so without an approved indication. Overusing PPIs is known to involve a tremendous cost in financial terms, and many western countries have reported high spending on these medicines.
We conducted a narrative review to evaluate PPI deprescription strategies carried out entirely or in collaboration with primary care and to identify factors that could influence the success of these strategies.
This review was conducted in November 2022, following PRISMA guidelines. Four databases were searched: PubMed, Web of Science, Scopus and CINAHL Complete, using the MeSH terms 'proton pump inhibitors' AND 'deprescriptions'.
The search with the established criteria found eight studies. The different success rates obtained by the various studies analysed in this review may be due to the different methodologies used when establishing the protocols, sample selection and monitoring of the results.
We can conclude that the two factors related to the most successful strategies were a) the clarity and simplicity of the de-escalation protocols, in which patients were instructed on the measures to follow in the event of the reappearance of symptoms, and b) the training of the physicians responsible for deprescribing. Long-term conclusions cannot be drawn about the effectiveness of these protocols, given that the studies are limited in time. Other barriers to generalizing the results are the small sample size and the absence of control groups.
The relationship between race and biology is complex. In contemporary medical science, race is a social construct that is measured via self‐identification of study participants. But even though race ...has no biological essence, it is often used as variable in medical guidelines (e.g., treatment recommendations specific for Black people with hypertension). Such recommendations are based on clinical trials in which there was a significant correlation between self‐identified race and actual, but often unmeasured, health‐related factors such as (pharmaco)genetics, diet, sun exposure, etc. Many teachers are insufficiently aware of this complexity. In their classes, they (unintentionally) portray self‐reported race as having a biological essence. This may cause students to see people of shared race as biologically or genetically homogeneous, and believe that race‐based recommendations are true for all individuals (rather than reflecting the average of a heterogeneous group). This medicalizes race and reinforces already existing healthcare disparities. Moreover, students may fail to learn that the relation between race and health is easily biased by factors such as socioeconomic status, racism, ancestry, and environment and that this limits the generalizability of race‐based recommendations. We observed that the clinical case vignettes that we use in our teaching contain many stereotypes and biases, and do not generally reflect the diversity of actual patients. This guide, written by clinical pharmacology and therapeutics teachers, aims to help our colleagues and teachers in other health professions to reflect on and improve our teaching on race‐based medical guidelines and to make our clinical case vignettes more inclusive and diverse.
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.
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.
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, IC
-IC
=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.
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.
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