Eur J Clin Pharmacol -2000) 56: 733±738 DOI 10.1007/s002280000215 PHARMACOEPIDEMIOLOGY AND PRESCRIPTION EugeÁ ne P. van Puijenbroek á Antoine C. G. Egberts Eibert R. Heerdink á Hubert G. M. Leufkens Detecting drug±drug interactions using a database for spontaneous adverse drug reactions: an example with diuretics and non-steroidal anti-in¯ammatory drugs Received: 27 April 2000 / Accepted in revised form: 7 September 2000 / Published online: 7 November 2000 Ó Springer-Verlag 2000 Abstract Objective: Drug±drug interactionsare rela- interval -CI) 1.1±3.7], which may indicate an enhanced tively rarely reported to spontaneous reporting systems eect of concomitant drug use. -SRSs) for adverse drug reactions. For this reason, the Conclusion: The ®ndings illustrate that spontaneous traditional approach for analysing SRS has major limi- reporting systems have a potential for signal detection tationsfor the detection of drug±drug interactions.We and the analysis of possible drug±drug interactions. The developed a method that may enable signalling of these method described may enable a more active approach possible interactions, which are often not explicitly in the detection of drug±drug interactionsafter mar- reported, utilising reports of adverse drug reactions in keting. data sets of SRS. As an example, the in¯uence of con- comitant use of diuretics and non-steroidal anti-in¯am- Key words Drug±drug interaction á matory drugs -NSAIDs) on symptoms indicating a Pharmacovigilance á Spontaneous reporting system decreased ecacy of diuretics was examined using reportsreceived by the NetherlandsPharmacovigilance Foundation Lareb. Introduction Methods: Reportsreceived between 1 January 1990 and 1 January 1999 of patientsolder than 50 yearswere in- Since the early 1960s, spontaneous reporting systems cluded in the study. Cases were de®ned as reports with -SRSs) have been used to detect adverse drug reac- symptoms indicating a decreased ecacy of diuretics, tions -ADRs) after marketing of drugs. Nowadays, non-cases as all other reports. Exposure categories were these reporting systems play a major role in pharma- the useof NSAIDsor diureticsversusthe useof neither covigilance [1]. Since the size of data sets is increasing, of these drugs. The in¯uence of the combined use of automated signal generation may be a promising tool both drugs was examined using logistic regression for selecting possible combinations of ADRs and analysis. Results: The odds ratio of the statistical inter- drugsthat might be worthwhile analysing in more action term of the combined use of both drugs was detail [2, 3, 4]. For signal detection concerning possi- increased [adjusted odds ratio 2.0, 95% con®dence ble unexpected ADRs, various measures of dispro- portionality can be used, including reporting odds ratios-RORs)[5, 6]. The basic principle of looking for disproportionality can be extended to the detection of drug±drug interac- E. P. van Puijenbroek -&) NetherlandsPharmacovigilance Foundation Lareb, tions, which are generally more dicult to detect. Usu- Goudsbloemvallei 7, 5237 MH's-Hertogenbosch, ally a drug±drug interaction might be suspected in the the Netherlands event that similar substances have proven to cause a Tel.: +31-73-6469707; Fax: +31-73-6426136 similar interaction. If this is not the case, detection e-mail: [email protected] becomesmore complicated. In the event a drug±drug A. C. G. Egberts1 á E. R. Heerdink á H. G. M. Leufkens interaction isunexpected given the previousknowledge, Department of Pharmacoepidemiology and Pharmacotherapy, it israrely reported to a SRS. Furthermore, in individual Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands patients, it is usually not clear whether ADRs arise directly from the use of a certain drug or that the ADR Present address: 1Hospital Pharmacy Midden-Brabant, concerned isin fact the resultof an underlying phar- TweeSteden Hospital and St. Elisabeth Hospital, macodynamic or pharmacokinetic drug±drug interac- Tilburg, the Netherlands tion. In particular in the elderly, additional factorssuch 734 as co-morbidity and multiple drug use may be present, ADRs were de®ned as cases. Non-cases were de®ned as all other enhancing the number of possible explanations of a reports. certain unexpected clinical event. In pre-marketing trials, patients with multiple drug use are usually excluded, Exposure categories which makesthe detection of drug±drug interactionsin the post-marketing period even more important. Information about concomitant drug use is requested on the In the event of a drug±drug interaction, one drug reporting forms. For the vast majority of the reports Lareb has the patients' drug dispensing history from community pharmacies. All in¯uencesthe eect of another drug. Thismay sub- drugs in use at the moment the ADR occurred were considered sequently cause an increase or decrease in the number possible causes of the ADR. If a drug was used to treat the ADR it of reported ADRsof the latter drug. By analysing isnot listedasconcomitant medication. The reporting health individual reports, it is usually dicult to recall professionals give an indication which drug is considered the sus- pected drug. Usually, however, only one drug is indicated. Since we whether speci®c concomitant medication was also used were looking for drug±drug interactions, we therefore made no in similar reports. An automated statistical approach distinction between suspected and non-suspected medication. All may be helpful in analysing large numbers of these medication that the patient wasusingaccording the medication reports and in revealing the existence of these complex history on the calendar date of the event was considered. relationships. The in¯uence of the combined use of Exposure categories were the use of NSAIDs [WHO Anatomical Therapeutic Chemical -ATC) classi®cation code M01A], or diuretics drugs can be studied by introducing a statistical in- -ATC code C03) versus the use of neither of these drugs. Covariates teraction term in a logistic model for the calculation used in the analysis were: type of health professional that reported of RORs, as was shown in a previous study by our the ADR -either pharmacist or physician), year of reporting, age and group [7]. gender of the patient involved, the use of antidiabetic drugs -ATC code A10), cardiac glycosides -ATC code C01), antihypertensive Asan example of the approach described, in reports drugs-ATC code C02), peripheral vasodilatatingdrugs-ATC code received by the NetherlandsPharmacovigilance Foun- C04), b-blocking agents-ATC code C07), calcium channel blocking dation Lareb, the concomitant use of both diuretics and agents-ATC code C08) and drugsacting on the renin angiotensin non-steroidal anti-in¯ammatory drugs -NSAIDs) was aldosterone system -RAAS, ATC code C09). associated with the occurrence of symptoms that may point towardsa reduction of the therapeutic eectsof Statistical analysis diuretics. This drug±drug interaction has been described in several case reports and studies [8, 9, 10, 11, 12, 13, 14, For the analysis, the following logistic model was used: 15, 16, 17, 18, 19, 20, 21]. Ã log odds b0 b1N b2D b3N D bnÀxCnÀx where N=NSAIDs, D=diuretics, Cn±x=dierent covariates, i.e. age, source and reporting year. Methods A statistically signi®cant value of the interaction term b3 indi- catesan additional eect of concomitant useof diureticsand Setting and design NSAIDs. Probability -P) values of 0.05 or less were considered statistically signi®cant. For all analyses the statistical package SPSS The NetherlandsPharmacovigilance Foundation Lareb isthe 8.0 wasused. national centre for submitting spontaneous reports of suspected ADRs originating from health care professionals in the Netherlands [22]. These reports are considered to be a re¯ection of the ADRs that occur in daily practice, taking into account the variousdegrees Results of underreporting that are an inherent attribute of spontaneous reporting [23, 24, 25, 26]. The analysis of drug±drug interactions is From January 1990 until January 1999, Lareb received based on the assumption that speci®c ADRs may occur more fre- quently when both drugs are used concomitantly in comparison 9907 reportsof patientsaged over 50 years.Eighty-®ve with separate use [7, 27]. This speci®c increase in reports is assumed reportswere excluded becausethe age or gender of the to be re¯ected in the number of reportsto Lareb. patient wasnot known. A total of 9822 reports,which All reportssubmittedto Lareb between 1 January 1990 and 1 were separated into 305 cases and 9517 non-cases, were January 1999 of patientsolder than 50 yearswere included in the analysis. Data concerning ages and genders of the patients had to included in the analysis. be available. Characteristics of cases and non-cases concerning age, gender, source of the reports and the use of several cardiac Selection of cases and non-cases drugs are provided in Table 1. Among the cases, the number of femalesand the age of the patients- P<0.01, t- A decrease in the ecacy of diuretics may express itself as the test) is signi®cantly higher. Also the use of diuretics, occurrence of oedema or signs indicating the onset or worsening NSAIDs, antihypertensive drugs and calcium channel of congestive heart failure -CHF). After being received by Lareb, the reported possible ADR is coded by a quali®ed assessor using blocking agents was more frequent among the cases. the World Health Organization -WHO) Adverse Drug Reaction There were no dierences concerning the use of insulin Terminology [28]. The presence of one or more of the following and oral antidiabetic drugs, cardiac glycoside drugs, pe- WHO preferred termson the reportswastherefore consideredas ripheral vasodilatating drugs, beta-blocking agents, and an indication for thissituation:`oedema', `oedema dependent', `oedema generalised', `oedema peripheral', `cardiac failure', `car- drugsacting on the RAAS in the medication history. diac failure left', `cardiac failure right', `pulmonary oedema' and Among the cases, the following suspected ADRs were `oedema legs'. Reports that mentioned one of the aforementioned mentioned on the reporting forms: oedema -n=68), 735 Table 1 Characteristics of cases and non-cases.