Clinical safety of metamizole

Abstract

Metamizole is an old analgesic agent. Its use is highly controversial due to its capacity to induce agranulocytosis, a rapid and severe fall of neutrophil granulocytes with risk of fatal outcome. Despite of this debate and withdrawal from the market in several countries, the use of metamizole increased in the last ten years in Switzerland as well as in Germany. The goal of this PhD-thesis project was therefore to improve our understanding of the clinical toxicity of metamizole. The work should contribute to a better understanding of the risk-benefit profile and promote the safe use of metamizole. In a first approach, we descriptively analyzed worldwide pharmacovigilance data concerning adverse effects related to metamizole. The main objective was to characterize spontaneously reported cases of hematological adverse drug reactions associated with metamizole as suspected drug regarding appearance, course, and severity of the reactions. The worldwide case safety reports were selected from the WHO Global Individual Case Safety Report Database (VigibaseTM), the national reports from the National Pharmacovigilance Database from Swissmedic. This allowed a comparison of reported hematological adverse drug reactions on a national and international level. A total of 1417 international and 77 Swiss reports were analyzed. Around 52% of the international and 33% of the Swiss metamizole-associated hematological ADR occurred within a latency time of ≤7 days. More women were reported. The annual number of hematological reports and those with fatal outcomes increased over the last years parallel to metamizole sales figures. The minimal incidence rate of agranulocytosis was 0.46-1.63 cases per million person-days of use (2006-2012) estimated via sales figures and number of reports. Female sex, old age, pancytopenia, and co-medication with methotrexate were striking characteristics of the 7 Swiss fatal cases. Early detection of myelotoxicity and avoidance of other myelotoxic substances like methotrexate (also at an immunosuppressive dose) are important measures for preventing fatalities. In a second study, we retrospectively performed a case-control study of metamizole associated leucopenias. We focused on the search of risk factors for the development of metamizole-induced white blood cell disorders. Fifty-seven cases and 139 controls were identified. Of the 57 cases, 32 were post-operative (post-OP) which were compared to age-, sex- and ward-matched post-OP controls (n= 64). The remaining cases (n= 25) were compared to sex-matched, non-post-OP controls (n= 75). The number of patients with a positive allergy history was higher among post-OP cases than controls (p= 0.0015) as was the number with previous leucopenic episodes (p= 0.03). The prevalence of diagnosed hepatitis C infection was 7% among all cases compared to 1% among all controls (p= 0.01). The use of concomitant cytostatic agents (even at immunosuppressive doses) was significantly higher among non-post-OP cases than controls (p= 0.007), with a trend to this distribution among post-OP patients. We concluded that a history of allergies, leucopenic episodes, hepatitis C infection and concomitant cytostatic agents are possible risk factors leucopenia associated with metamizole use. The third project, a clinical study about the renal safety of metamizole, dealt with a possible advantage of metamizole. The aim of this study was to examine the effects of metamizole on renal function (inulin clearance and urinary excretion of sodium and of the prostacyclin metabolite 6-keto-PGF1α in healthy, salt-depleted volunteers) in comparison with the non-specific COX-inhibitor naproxen. If it could be shown that metamizole does not have negative effects on renal function, its use in patients with impaired renal function who cannot be treated with NSAIDs would be supported. After single and repetitive dosing, neither metamizole nor naproxen had a significant effect on inulin clearance or sodium excretion. After repetitive dosing, there was a trend for decreased sodium excretion after naproxen but not after metamizole. Both metamizole and naproxen inhibited renal 6-keto-PGF1α excretion starting 2 hours after ingestion and lasting the entire dosing period during repetitive dosing, suggesting that metamizole inhibits renal prostaglandin synthesis similarly to naproxen. Therefore, renal excretion of 6-keto-PGF1α may not be the ideal marker to differentiate between the renal adverse effects of NSAIDs and metamizole. Nevertheless, in healthy, sodium-depleted subjects, metamizole had no significant effect on inulin clearance or renal sodium excretion, whereas there was a trend to a decreased sodium excretion after repetitive naproxen dosing. Further studies in more susceptible individuals have to be conducted in order to answer the question whether the effect of metamizole on renal function is different compared to NSAIDs.