Incidence rate and pattern of clinically relevant potential drug-drug interactions in a large outpatient population of a developing country

Ehsan Nabovati, Hasan Vakili-Arki, Zhila Taherzadeh, Mohammad Reza Saberi, Ameen Abu-Hanna, Saeid Eslami


The objective of this study was to determine incidence rate, type, and pattern of clinically relevant potential drug-drug interactions (pDDIs) in a large outpatient population of a developing country. A retrospective, descriptive cross-sectional study was conducted on outpatients’ prescriptions in Khorasan Razavi province, Iran, over 12 months. A list of 25 clinically relevant DDIs, which are likely to occur in the outpatient setting, was used as the reference. Most frequent clinically relevant pDDIs, most common drugs contributing to the pDDIs, and the pattern of pDDIs for each medical specialty were determined. Descriptive statistics were used to report the results. In total, out of 8,169,142 prescriptions, 6,096 clinically relevant pDDIs were identified. The most common identified pDDIs were theophyllines-quinolones, warfarin-nonsteroidal anti-inflammatory drugs, benzodiazepines-azole antifungal agents, and anticoagulants-thyroid hormones. The most common drugs contributing to the identified pDDIs were ciprofloxacin, theophylline, warfarin, aminophylline, alprazolam, levothyroxine, and selegiline. While the incidence rate of clinically relevant pDDIs in prescriptions of general practitioners, internists, and cardiologists was the highest, the average pDDI incidence per 10,000 prescriptions of pulmonologists, infectious disease specialists, and cardiologists was highest. Although a small proportion of the analyzed prescriptions contained drug pairs with potential for clinically relevant DDIs, a significant number of outpatients have been exposed to the adverse effects associated with these interactions. It is recommended that in addition to training physicians and pharmacists, other effective interventions such as computerized alerting systems and electronic prescribing systems be designed and implemented.

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Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003;289:1652-1658.

Marengoni A, Pasina L, Concoreggi C, Martini G, Brognoli F, Nobili A, et al. Understanding adverse drug reactions in older adults through drug-drug interactions. Eur J Intern Med. 2014;25:843-846.

Leone R, Magro L, Moretti U, Cutroneo P, Moschini M, Motola D, et al. Identifying adverse drug reactions associated with drug-drug interactions: data mining of a spontaneous reporting database in Italy. Drug Saf. 2010;33:667-675.

Jankel CA, Fitterman LK. Epidemiology of drug-drug interactions as a cause of hospital admissions. Drug Saf. 1993;9:51-59.

McDonnell PJ, Jacobs MR. Hospital admissions resulting from preventable adverse drug reactions. Ann Pharmacother. 2002;36:1331-1336.

Peyriere H, Cassan S, Floutard E, Riviere S, Blayac JP, Hillaire-Buys D, et al. Adverse drug events associated with hospital admission. Ann Pharmacother. 2003;37:5-11.

Askari M, Eslami S, Louws M, Dongelmans D, Wierenga P, Kuiper R, et al. Relevance of drug-drug interaction in the ICU - perceptions of intensivists and pharmacists. Stud Health Technol Inform. 2012;180:716-720.

Slight SP, Seger DL, Nanji KC, Cho I, Maniam N, Dykes PC, et al. Are we heeding the warning signs? Examining providers' overrides of computerized drug-drug interaction alerts in primary care. PLoS One. 2013;8:e85071.

Nikolic BS, Ilic MS. Assessment of the consistency among three drug compendia in listing and ranking of drug-drug interactions. Bosn J Basic Med Sci. 2013;13:253-258.

Vitry AI. Comparative assessment of four drug interaction compendia. Br J Clin Pharmacol. 2007;63:709-714.

Malone DC, Abarca J, Hansten PD, Grizzle AJ, Armstrong EP, Van Bergen RC, et al. Identification of serious drug-drug interactions: results of the partnership to prevent drug-drug interactions. J Am Pharm Assoc. 2004;44:142-151.

Aparasu R, Baer R, Aparasu A. Clinically important potential drug-drug interactions in outpatient settings. Res Social Adm Pharm. 2007;3:426-437.

Malone DC, Hutchins DS, Haupert H, Hansten P, Duncan B, Van Bergen RC, et al. Assessment of potential drug-drug interactions with a prescription claims database. Am J Health Syst Pharm. 2005;62:1983-1991.

Tragni E, Casula M, Pieri V, Favato G, Marcobelli A, Trotta MG, et al. Prevalence of the prescription of potentially interacting drugs. PLoS One. 2013;8:e78827.

Dirin MM, Mousavi S, Afshari AR, Tabrizian K, Ashrafi MH. Potential drug-drug interactions in prescriptions dispensed in community and hospital pharmacies in East of Iran. J Res Pharm Pract. 2014;3:104-107.

Patel PS, Rana DA, Suthar JV, Malhotra SD, Patel VJ. A study of potential adverse drug-drug interactions among prescribed drugs in medicine outpatient department of a tertiary care teaching hospital. J Basic Clin Pharm. 2014;5:44-48.

Teixeira JJ, Crozatti MT, dos Santos CA, Romano-Lieber NS. Potential drug-drug interactions in prescriptions to patients over 45 years of age in primary care, southern Brazil. PLoS One. 2012;7:e47062.

Nabovati E, Vakili-Arki H, Taherzadeh Z, Hasibian MR, Abu-Hanna A, Eslami S. Drug-drug interactions in inpatient and outpatient settings in Iran: a systematic review of the literature. Daru. 2014;22:52.

Antoniou T, Gomes T, Mamdani MM, Juurlink DN. Ciprofloxacin-induced theophylline toxicity: a population-based study. Eur J Clin Pharmacol. 2011;67:521-526.

Bem JL, Mann RD. Drug point: Danger of interaction between ciprofloxacin and theophylline. Br Med J (Clin Res Ed). 1988;296:1131.

Wijnands WJ, Vree TB. Interaction between the fluoroquinolones and the bronchodilator theophylline. J Antimicrob Chemother. 1988;22 Suppl C:109-114.

Tatro DS. Drug interaction facts 2015 : the authority on drug interactions: Saint Louis, Missouri : Wolters Kluwer Health; 2015. p. 241.

Baxter K, Preston CL. Stockley's Drug Interactions Pocket Companion. London: Pharmaceutical Press; 2013. p. 418.

von Moltke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, et al. Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J Clin Pharmacol. 1996;36: 783-791.

Penning-van Beest F, Erkens J, Petersen KU, Koelz HR, Herings R. Main comedications associated with major bleeding during anticoagulant therapy with coumarins. Eur J Clin Pharmacol. 2005;61:439-444.

Chan TY. Adverse interactions between warfarin and nonsteroidal antiinflammatory drugs: mechanisms, clinical significance, and avoidance. Ann Pharmacother. 1995;29:1274-1283.

Knijff-Dutmer EA, Schut GA, van de Laar MA. Concomitant coumarin-NSAID therapy and risk for bleeding. Ann Pharmacother. 2003;37:12-16.

Schelleman H, Bilker WB, Brensinger CM, Wan F, Yang Y-X, Hennessy S. Fibrate/statin initiation in warfarin users and gastrointestinal bleeding risk. Am J Med. 2010;123:151-157.


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