Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study

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Abstract

Aim

To analyze potential and actual drug-drug interactions reported to the Spontaneous Reporting Database of the Croatian Agency for Medicinal Products and Medical Devices (HALMED) and determine their incidence.

Methods

In this retrospective observational study performed from March 2005 to December 2008, we detected potential and actual drug-drug interactions using interaction programs and analyzed them.

Results

HALMED received 1209 reports involving at least two drugs. There were 468 (38.7%) reports on potential drug-drug interactions, 94 of which (7.8% of total reports) were actual drug-drug interactions. Among actual drug-drug interaction reports, the proportion of serious adverse drug reactions (53 out of 94) and the number of drugs (n = 4) was significantly higher ( P < 0.001) than among the remaining reports (580 out of 1982; n = 2, respectively). Actual drug-drug interactions most frequently involved nervous system agents (34.0%), and interactions caused by antiplatelet, anticoagulant, and non-steroidal anti-inflammatory drugs were in most cases serious. In only 12 out of 94 reports, actual drug-drug interactions were recognized by the reporter.

Conclusion

The study confirmed that the Spontaneous Reporting Database was a valuable resource for detecting actual drug-drug interactions. Also, it identified drugs leading to serious adverse drug reactions and deaths, thus indicating the areas which should be in the focus of health care education.

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Most cited references 43

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The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group.

D Bates, N Spell, D J Cullen … (1997)

To assess the additional resource utilization associated with an adverse drug event (ADE). Nested case-control study within a prospective cohort study. The cohort included 4108 admissions to a stratified random sample of 11 medical and surgical units in 2 tertiary-care hospitals over a 6-month period. Cases were patients with an ADE, and the control for each case was the patient on the same unit as the case with the most similar pre-event length of stay. Postevent length of stay and total costs. Incidents were detected by self-report stimulated by nurses and pharmacists and by daily chart review, and were classified as to whether they represented ADEs. Information on length of stay and charges was obtained from billing data, and costs were estimated by multiplying components of charges times hospital-specific ratios of costs to charges. During the study period, there were 247 ADEs among 207 admissions. After outliers and multiple episodes were excluded, there were 190 ADEs, of which 60 were preventable. In paired regression analyses adjusting for multiple factors, including severity, comorbidity, and case mix, the additional length of stay associated with an ADE was 2.2 days (P=.04), and the increase in cost associated with an ADE was $3244 (P=.04). For preventable ADEs, the increases were 4.6 days in length of stay (P=.03) and $5857 in total cost (P=.07). After adjusting for our sampling strategy, the estimated postevent costs attributable to an ADE were $2595 for all ADEs and $4685 for preventable ADEs. Based on these costs and data about the incidence of ADEs, we estimate that the annual costs attributable to all ADEs and preventable ADEs for a 700-bed teaching hospital are $5.6 million and $2.8 million, respectively. The substantial costs of ADEs to hospitals justify investment in efforts to prevent these events. Moreover, these estimates are conservative because they do not include the costs of injuries to patients or malpractice costs.

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Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.

Mikko Niemi, T Backman, Pertti Neuvonen (2006)

Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic disease. The benefits of statins are well documented. However, lipid-lowering drugs may cause myopathy, even rhabdomyolysis, the risk of which is increased by certain interactions. Simvastatin, lovastatin, and atorvastatin are metabolized by cytochrome P450 (CYP) 3A4 (simvastatin acid is also metabolized by CYP2C8); their plasma concentrations and risk of myotoxicity are greatly increased by strong inhibitors of CYP3A4 (eg, itraconazole and ritonavir). Weak or moderately potent CYP3A4 inhibitors (eg, verapamil and diltiazem) can be used cautiously with small doses of CYP3A4-dependent statins. Cerivastatin is metabolized by CYP2C8 and CYP3A4, and fluvastatin is metabolized by CYP2C9. The exposure to fluvastatin is increased by less than 2-fold by inhibitors of CYP2C9. Pravastatin, rosuvastatin, and pitavastatin are excreted mainly unchanged, and their plasma concentrations are not significantly increased by pure CYP3A4 inhibitors. Cyclosporine (INN, ciclosporin) inhibits CYP3A4, P-glycoprotein (multidrug resistance protein 1), organic anion transporting polypeptide 1B1 (OATP1B1), and some other hepatic uptake transporters. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. These effects of cyclosporine and gemfibrozil explain the increased plasma statin concentrations and, together with pharmacodynamic factors, the increased risk of myotoxicity when coadministered with statins. Inhibitors of OATP1B1 may decrease the benefit/risk ratio of statins by interfering with their entry into hepatocytes, the site of action. Lipid-lowering drugs can be involved also in other interactions, including those between enzyme inducers and CYP3A4 substrate statins, as well as those between gemfibrozil and CYP2C8 substrate antidiabetics. Knowledge of the pharmacokinetic and pharmacodynamic properties of lipid-lowering drugs and their interaction mechanisms helps to avoid adverse interactions, without compromising therapeutic benefits.

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Systems analysis of adverse drug events. ADE Prevention Study Group.

M. J. Cooper, D. Cullen, D Bates … (1995)

To identify and evaluate the systems failures that underlie errors causing adverse drug events (ADEs) and potential ADEs. Systems analysis of events from a prospective cohort study. All admissions to 11 medical and surgical units in two tertiary care hospitals over a 6-month period. Errors, proximal causes, and systems failures. Errors were detected by interviews of those involved. Errors were classified according to proximal cause and underlying systems failure by multidisciplinary teams of physicians, nurses, pharmacists, and systems analysts. During this period, 334 errors were detected as the causes of 264 preventable ADEs and potential ADEs. Sixteen major systems failures were identified as the underlying causes of the errors. The most common systems failure was in the dissemination of drug knowledge, particularly to physicians, accounting for 29% of the 334 errors. Inadequate availability of patient information, such as the results of laboratory tests, was associated with 18% of errors. Seven systems failures accounted for 78% of the errors; all could be improved by better information systems. Hospital personnel willingly participated in the detection and investigation of drug use errors and were able to identify underlying systems failures. The most common defects were in systems to disseminate knowledge about drugs and to make drug and patient information readily accessible at the time it is needed. Systems changes to improve dissemination and display of drug and patient data should make errors in the use of drugs less likely.

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Author and article information

Journal

Journal ID (nlm-ta): Croat Med J

Journal ID (publisher-id): CMJ

Title: Croatian Medical Journal

Publisher: Croatian Medical Schools

ISSN (Print): 0353-9504

ISSN (Electronic): 1332-8166

Publication date (Print): October 2011

Volume: 52

Issue: 5

Pages: 604-614

Affiliations

[1 ]Pharmacovigilance Department, Agency for Medicinal Products and Medical Devices, Zagreb, Croatia

[2 ]Centre for Applied Pharmacy, Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia

[3 ]Department of Laboratory Diagnostics, University School of Medicine and University Hospital Center, Zagreb, Croatia

[4 ]Agency for Medicinal Products and Medical Devices, Zagreb, Croatia

Author notes

Correspondence to:  Nikica Mirošević Skvrce Pharmacovigilance Department Agency for Medicinal Products and Medical Devices (HALMED) Ksaverska cesta 4 HR 10 000 Zagreb, Croatia  nikica.mirosevic@ 123456halmed.hr

Article

Publisher ID: CroatMedJ_52_0604

DOI: 10.3325/cmj.2011.52.604

PMC ID: 3195969

PubMed ID: 21990078

SO-VID: 20c1bf3b-8405-4ed1-91c7-8f7522dff1f2

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Adverse drug reactions caused by drug-drug interactions reported to Croatian Agency for Medicinal Products and Medical Devices: a retrospective observational study

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Drug Repurposing Research Collection

Most cited references 43

The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group.

Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance.

Systems analysis of adverse drug events. ADE Prevention Study Group.

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