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

Cuevas, Carlos De las; Sanz, Emílio J.; Leon, José de

doi:10.1016/j.schres.2023.05.004

Cited by 14 publications

(13 citation statements)

References 52 publications

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“…Then review the information that US clozapine prescribers do not associate clozapine with TdP, but clozapine blocks the cardiac channels in a concentration-related way and is associated with a large number of sudden unexplained deaths according to the US pharmacovigilance data. The number of US fatal outcomes in clozapine patients associated with agranulocytosis is much smaller than the number associated with sudden deaths or pneumonia 5 …”

Section: Discussionmentioning

confidence: 94%

“…Clozapine was introduced before the Food and Drug Administration was concerned about TdP or its marker QTc prolongation, so the meta-analysis on QTc prolongation does not include clozapine data 2 . Using an in vitro model that may reflect clozapine concentrations at the high end of the therapeutic range, Le Marois et al 5 found clozapine inhibited 7 cardiac ion channels (5 potassium, 1 sodium, and 1 calcium). In an animal model, Liu et al 4 compared 32 drugs; clozapine was considered to be in the intermediate risk group, which also included other antipsychotics: chlorpromazine, droperidol, pimozide, and risperidone.…”

Section: Response From An Expertmentioning

confidence: 99%

“…All forms of severe neutropenia accounted for only 218 fatal outcomes or 2.3% of 9587 deaths. Sudden death accounted for 111 deaths, and another similar label “cardiac arrest” accounted for 415 fatal outcomes 5 …”

Section: Response From An Expertmentioning

confidence: 99%

“…The more surprising US pharmacovigilance finding is that pneumonia was extremely lethal in US clozapine patients with 559 fatal outcomes comprising a relative lethality of 39% based on 1438 pneumonia reports 5 . It has not been studied in clozapine patients, but arrhythmias may be a frequent mechanism of death in schizophrenia patients with pneumonia 6 …”

Section: Response From An Expertmentioning

confidence: 99%

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de Leon

2024

J Clin Psychopharmacol

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Section: Discussionmentioning

confidence: 94%

Section: Response From An Expertmentioning

confidence: 99%

Section: Response From An Expertmentioning

confidence: 99%

Section: Response From An Expertmentioning

confidence: 99%

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de Leon

2024

J Clin Psychopharmacol

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“…Some of the serious adverse drug reactions of clozapine, other than agranulocytosis, are severe constipation complicated with ileus, myocarditis, and pneumonia, 33 which are now more relatively frequent than agranulocytosis due to increased pharmacovigilance. 34 Regarding pneumonia specifically, numerous hypotheses regarding its onset have been discussed during recent years, mostly focusing on immunogloblins depletion and increasing the interleukin-1 receptor antagonist, other than hypersalivation and sedation that could lead to acquiring pneumonia. 35 Regarding myocarditis, its reported incidence of myocarditis varies in the literature (0.06%-3.88%).…”

Section: Discussionmentioning

confidence: 99%

Clozapine-Associated Agranulocytosis

Magistri,

Mellini

2023

J Clin Psychopharmacol

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Background Clozapine is a very effective therapeutic option for schizophrenic disorders that have been refractory to most other therapies. This extremely positive aspect clashes easily with an adverse effect of the drug that is deemed to be a very dangerous one: agranulocytosis. We asked whether the mandatory strict hematological follow-up prescribed in the black box warning of clozapine's label is proportioned to the actual incidence of agranulocytosis, considering that is the main reason that such a drug is often used only late in the treatment course. Methods We carried out a systematic review of reports examining clozapine administration and agranulocytosis incidence. We specifically selected those where mild and moderate neutropenia was not used as a trigger to stop administration of clozapine, to better estimate the sheer incidence of agranulocytosis when clozapine was continued even with mild hematological effect, where detected. We used PubMed, MEDLINE, EMBASE, Cochrane, and ScienceDirect databases to identify clinical studies conducted between January 1975 and April 2023. Results We included 14 studies, mostly retrospective ones, that examined the incidence of hematological adverse effects in patients using clozapine. A total of 2354 subjects were included. The mean age of the subjects was 33.5 years. The mean duration of observation of subjects who took clozapine was 800 days, with a mean daily dose of 319.5 mg per day. Of the 2354 subjects examined, we found that 11 of them experienced agranulocytosis (0.47%). Conclusions These results suggest the evidence of a lower incidence of agranulocytosis than previously estimated and are in line with more recent meta-analyses. We may therefore think that clinical practice may demand a revision of the approach that both psychiatrists and supervising organizations often take when talking about clozapine.

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When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis

Qubad,

Dupont,

Hahn

et al. 2024

CNS Drugs

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Clozapine-induced myocarditis (CIM) is among the most important adverse events limiting the use of clozapine as the most effective treatment for schizophrenia. CIM necessitates the immediate termination of clozapine, often resulting in its permanent discontinuation with considerable detrimental effects on patients’ psychopathology and long-term outcome. Consequently, a clozapine re-challenge after CIM is increasingly regarded as a viable alternative, with published reports indicating a success rate of approximately 60%. However, published cases of re-challenges after CIM remain limited. Here, we provide a narrative review of the current state of research regarding the epidemiology, pathophysiology, risk factors, diagnosis and clinical management of CIM as well as a synthesis of current recommendations for re-challenging patients after CIM. This includes a step-by-step guide for this crucial procedure based on the current evidence regarding the pathophysiology and risk factors for CIM. Slow dose titration regimes and addressing risk factors including concomitant valproate and olanzapine are crucial both to prevent CIM and to ensure a safe and successful re-challenge. Furthermore, we discuss the utility of C-reactive protein, troponin, N-terminal-pro hormone and brain natriuretic peptide, therapeutic drug-monitoring and cardiac magnetic resonance imaging for CIM screening and diagnosis as well as for post-CIM re-challenges.

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

Cited by 14 publications

References 52 publications

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Clozapine-Associated Agranulocytosis

When, Why and How to Re-challenge Clozapine in Schizophrenia Following Myocarditis

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