Agranulozytose nach Metamizol-Einnahme – ein unterschätztes Risiko?

Schinz, K; Waldfahrer, Frank; Wüst, Wolfgang; Iro, Heinrich

doi:10.1055/a-1190-4445

Cited by 5 publications

(5 citation statements)

References 13 publications

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“…Indeed, acute infections are more frequently observed in patients with metamizole-associated neutropenia than in metamizole-tolerant patients [18]. The combination of fever, throat pain and tonsillitis are the typical triad of symptoms for agranulocytosis, which were as well observed in patient #1 in our study [19,20]. Similar to her case, some patients experience ulcerating tonsillitis and abscess removal is needed.…”

Section: Discussionsupporting

confidence: 80%

NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis

Radulovic¹,

Dogan²,

Dohna-Schwake³

et al. 2021

Pharmacogenetics and Genomics

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Metamizole is a widely prescribed NSAID with excellent analgesic and antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe agranulocytosis. We here describe three patients with metamizole-associated agranulocytosis. Patient #1 suffered from agranulocytosis and tonsillitis followed by severe sepsis by Streptococcus pneumoniae and Epstein-Barr virus reactivation. Her dizygotic twin sister (patient #2) also suffered from agranulocytosis after a surgical intervention. Patient #3 initially had a tonsillitis and also developed neutropenia after metamizole intake. For all patients, pharmacogenetic diagnostic for the genes CYP2C9, CYP2C19 and NAT2, which are involved in metamizole metabolism and degradation of toxic metabolites, was initiated. Pharmacogenetic analysis revealed NAT2 slow acetylator phenotype in all three patients. Additionally, patient #2 is an intermediate metabolizer for CYP2C19 and patient #3 is a poor metabolizer for CYP2C9. Impairment of these enzymes causes a reduced degradation of toxic metabolites, for example, 4-methylaminoantipyrine (4-MAA) or 4-aminoantipyrine. The metabolite 4-MAA can complex with hemin, which is an early breakdown product during hemolysis. Hemolysis is often observed during invasive infections or after surgical procedures. It is known that the 4-MAA/hemin complex can induce cytotoxicity in the bone marrow and interrupt granulocyte maturation. In conclusion, metamizole-induced agranulocytosis most likely was a consequence of the underlying genetical predisposition, that is, polymorphisms in the genes NAT2, CYP2C9 and CYP2C19. Hemolysis may have increased the toxicity of metamizole metabolites.

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Section: Discussionsupporting

confidence: 80%

NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis

Radulovic¹,

Dogan²,

Dohna-Schwake³

et al. 2021

Pharmacogenetics and Genomics

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“…As the studies cover several aspects related to the safety implications of dipyrone therapy, a didactic division has been made to group the issues in the discussion: dipyrone in children [22][23][24][25][26][27], dipyrone during pregnancy [28], dipyrone and blood dyscrasias [29][30][31][32][33][34], dipyrone in specific diseases [35][36][37][38][39][40][41][42][43][44], in addition to anaphylactic reactions and general adverse effects of dipyrone [45][46][47][48][49][50][51]. About the quality of the studies, it is worth mentioning the scarcity of clinical trials, with the majority being of observational retrospective or cohort design (n = 27).…”

Section: Resultsmentioning

confidence: 99%

“…For professionals involved with patient follow-up, it is worth discussing the timing of blood dyscrasia development from the start of dipyrone treatment. Acute reactions, within 7 days, occurred in 34.7% [33], 30.5% [31], and 12.5% [32] of the samples evaluated. More attention should be given to cases of re-exposure or concomitant use with other drugs, in which this period may be even shorter [33].…”

Section: Dipyrone and Blood Dyscrasiasmentioning

confidence: 97%

“…Another retrospective study, also in Germany, evaluated the evolution of a sample of only eight patients who developed dipyrone agranulocytosis in an otolaryngology department. It was identified that 4 (50%) of them required ICU admission and one (12.5%) progressed to multiple organ failure [32]. Also, a retrospective analysis of spontaneous reports from different European countries in the Eudra Vigilance database between 1985 and 2017 identified that, of the 1,448 reports of metamizole associated agranulocytosis observed, prolonged hospitalizations occurred in 75.1% of cases, with life-threatening in 43%, fatal events in 16.2% and with a higher risk ratio being found for elderly patients or those who had received other associated drugs such as methotrexate [33].…”

Section: Dipyrone and Blood Dyscrasiasmentioning

confidence: 99%

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One hundred years of dipyrone (metamizole): the recent evidence on its safety

Malheiro

Viana²,

Nascimento³

et al. 2023

PRW

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Dipyrone is a non-opioid analgesic drug used for fever and many types of pain. Due to the risk of induced agranulocytosis, it was banned in the early 1980s in several countries, but is still widely used in Brazil, Mexico, China and others. This study is a systematic review of literature focusing on the recent evidence about dipyrone safety. To this, a literature search was performed for epidemiological studies published between 2015 and 2022, in English, German, Portuguese, and Spanish languages. From the 30 articles that met the inclusion criteria, most of them consisted in observational studies (n = 27). In children, the frequency of adverse events with dipyrone is low, but can affect the renal and circulatory systems. During pregnancy, the drug doesn't seem to be related to teratogenic abnormalities. Agranulocytosis is still a matter of debate. However, the occurrence is rare, with an estimated risk of 1:1,602. In adults, dipyrone is related to several adverse effects on renal, hepatic, respiratory and epidermal systems. Thus, dipyrone seems to have a low incidence of adverse effects, but some can be considered of high severity. Especially in children, elderly and patients who need treatment for long periods, other analgesic options should be evaluated.

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“…It is possible that serious complications could be avoided by performing routine control blood tests after the initial use of metamizole. However, routine venipuncture is likely to be difficult to perform on a day-to-day basis given the widespread use of metamizole in the outpatient setting [ 33 ]. Further complicating is the fact that the interval from metamizole application to hematologic complications varies greatly in the literature.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Simultaneously Induced Neutropenia and Hemolysis After a Single Metamizole Dose

et al. 2023

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Background and objective Metamizole is a non-opioid ampyrone sulfonate compound with potent analgesic, antipyretic, and spasmolytic effects. Agranulocytosis is a rare life-threatening complication of metamizole. Case Here, we present the case of a 62-year-old patient who developed agranulocytosis as well as hemolysis after a single administration of metamizole. Conclusion This case illustrates the inherent allergic potential of metamizole and its effects on different hematopoietic cell types. Key PointsAgranulocytosis and hemolysis occurred simultaneously as a result of the first and single administration of metamizole.It is unclear which individual factors determine the extent of a potential allergic reaction.Patients receiving metamizole for the first time may benefit from a close follow-up, in particular within the first few weeks.

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Agranulozytose nach Metamizol-Einnahme – ein unterschätztes Risiko?

Cited by 5 publications

References 13 publications

NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis

NAT2 polymorphisms as a cause of metamizole-induced agranulocytosis

One hundred years of dipyrone (metamizole): the recent evidence on its safety

Case Report: Simultaneously Induced Neutropenia and Hemolysis After a Single Metamizole Dose

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