Muscular Adverse Drug Reactions Associated with Proton Pump Inhibitors: A Disproportionality Analysis Using the Italian National Network of Pharmacovigilance Database

Sansone, Alice Capogrosso; Convertino, Irma; Galiulo, Maria Teresa; Salvadori, Stefano; Pieroni, Stefania; Knežević, Tamara; Mantarro, Stefania; Marino, Angela; Hauben, Manfred; Blandizzi, Corrado; Tuccori, Marco

doi:10.1007/s40264-017-0564-8

Cited by 19 publications

(18 citation statements)

References 83 publications

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“…Several studies have reported an association between myopathy and use of a PPI, and some mention an association between rhabdomyolysis and PPIs. [5][6][7]17 However, these reports are based on analyses of small numbers of patients with rhabdomyolysis. Various theories have been put forward to explain the mechanism of the muscle injury caused by PPIs, including induction of autoimmune antibodies, non-autoimmune antibody-mediated hypersensitivity reactions, electrolyte disorders, and autophagic myopathies, and it seems likely that all these mechanisms have an effect on muscle tissue.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 However, PPIs are known to increase the risk of various adverse events, including nephropathy, gastrointestinal infection, pneumonia, and fractures, which in turn increase the mortality risk. 3,4 According to several studies, [5][6][7] one of the severe adverse events caused by PPIs is myopathy. Although the mechanism of PPI-induced muscle injury is still unclear, various mechanisms have been suggested, including induction of autoimmune antibodies or electrolyte disorders as a result of long-term PPI use.…”

Section: Introductionmentioning

confidence: 99%

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Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases

et al. 2023

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Background: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis. Objective: To clarify whether use of PPIs increases the risk of rhabdomyolysis. Methods: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher’s exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher’s exact test and multiple logistic regression analysis were performed. Results: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin. Conclusion and Relevance: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases

et al. 2023

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“…Recently, Sansone et al . surveyed the Italian National Network of Pharmacovigilance Database and found that omeprazole was more frequently involved in reports of myopathy than any other nonstatin drugs . From this evidences omeprazole is the primary candidate that induced myopathy.…”

Section: Discussionmentioning

confidence: 99%

Translational High‐Dimensional Drug Interaction Discovery and Validation Using Health Record Databases and Pharmacokinetics Models

Chiang

Zhang

Wang

et al. 2017

Clin Pharma and Therapeutics

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Polypharmacy increases the risk of drug-drug interactions (DDIs). Combining epidemiological studies with pharmacokinetic modeling, we detected and evaluated high-dimensional DDIs among 30 frequent drugs. Multidrug combinations that increased the risk of myopathy were identified in the US Food and Drug Administration Adverse Event Reporting System (FAERS) and electronic medical record (EMR) databases by a mixture drug-count response model. CYP450 inhibition was estimated among the 30 drugs in the presence of 1 to 4 inhibitors using in vitro / in vivo extrapolation. Twenty-eight three-way and 43 four-way DDIs had significant myopathy risk in both databases and predicted increases in the area under the concentration-time curve ratio (AUCR) >2-fold. The high-dimensional DDI of omeprazole, fluconazole, and clonidine was associated with a 6.41-fold (FAERS) and 18.46-fold (EMR) increased risk of myopathy local false discovery rate (<0.005); the AUCR of omeprazole in this combination was 9.35. The combination of health record informatics and pharmacokinetic modeling is a powerful translational approach to detect high-dimensional DDIs.

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“…Moreover, it has been reported that long term use of PPIs can result in polymyositis, a type of chronic inflammation in the muscles [40]. Another possible, but rare side-effect of PPI use is rhabdomyolysis, a condition in which damaged muscle breaks down rapidly, and the breakdown product can effect kidney function [41,42]. To conclude, although generally considered safe, long-term use of PPIs could ultimately lead to deficiencies in several vitamins and minerals [36,37,43].…”

Section: Adverse Effects Of Long Term Use Of Ppismentioning

confidence: 99%

The Use of Proton Pump Inhibitors May Increase Symptoms of Muscle Function Loss in Patients with Chronic Illnesses

Vinke

Wesselink

Orten-Luiten

et al. 2020

IJMS

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Long-term use of proton pump inhibitors (PPIs) is common in patients with muscle wasting-related chronic diseases. We explored the hypothesis that the use of PPIs may contribute to a reduction in muscle mass and function in these patients. Literature indicates that a PPI-induced reduction in acidity of the gastrointestinal tract can decrease the absorption of, amongst others, magnesium. Low levels of magnesium are associated with impaired muscle function. This unwanted side-effect of PPIs on muscle function has been described in different disease backgrounds. Furthermore, magnesium is necessary for activation of vitamin D. Low vitamin D and magnesium levels together can lead to increased inflammation involved in muscle wasting. In addition, PPI use has been described to alter the microbiota’s composition in the gut, which might lead to increased inflammation. However, PPIs are often provided together with nonsteroidal anti-inflammatory drugs (NSAIDs), which are anti-inflammatory. In the presence of obesity, additional mechanisms could further contribute to muscle alterations. In conclusion, use of PPIs has been reported to contribute to muscle function loss. Whether this will add to the risk factor for development of muscle function loss in patients with chronic disease needs further investigation.

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Muscular Adverse Drug Reactions Associated with Proton Pump Inhibitors: A Disproportionality Analysis Using the Italian National Network of Pharmacovigilance Database

Abstract: This explorative study suggests that the class of PPIs could be involved in reports of muscular ADRs, rather than any other ADR, more frequently than any non-statin drug. Our results must be corroborated by further studies.

Cited by 19 publications

References 83 publications

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases

Proton Pump Inhibitors and Rhabdomyolysis: Analysis of Two Different Cross-Sectional Databases

Translational High‐Dimensional Drug Interaction Discovery and Validation Using Health Record Databases and Pharmacokinetics Models

The Use of Proton Pump Inhibitors May Increase Symptoms of Muscle Function Loss in Patients with Chronic Illnesses

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