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Published Online, 25 November 2008, www.theannals.com, DOI 10.1345/aph.1L255.
 The Annals of Pharmacotherapy: Vol. 42, No. 12, pp. 1737-1748. DOI 10.1345/aph.1L255
© 2008 Harvey Whitney Books Company.
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ONCOLOGY

Clinically Significant Drug-Drug Interactions Between Oral Anticancer Agents and Nonanticancer Agents: Profiling and Comparison of Two Drug Compendia

Chen-May Wong

Pharmacy Student, Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore

Yu Ko, PhD

Research Fellow, Department of Pharmacy, Faculty of Science, National University of Singapore

Alexandre Chan, PharmD BCPS BCOP

Assistant Professor, Department of Pharmacy, Faculty of Science, National University of Singapore; Clinical Pharmacist, Department of Pharmacy, National Cancer Centre, Singapore

Reprints: Dr. Chan, Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4, 16 Science Dr. 4, Singapore 117543, fax 65 6779 1554, phaac{at}nus.edu.sg.


   Abstract
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Methods
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 Discussion
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BACKGROUND: Use of oral anticancer agents is gaining wide acceptance in the treatment of cancer. However, patients receiving oral therapy are at high risk for drug-drug interactions (DDIs).

OBJECTIVE: To create a drug profile for each clinically significant DDI involving selected oral anticancer agents and evaluate the agreement between 2 commonly used DDI compendia: Drug Interaction Facts (DIF) 2008 and Micromedex DRUGDEX.

METHODS: DDI profiles were developed based on primary and tertiary literature reviews. DIF 2008 and Micromedex DRUGDEX were compared to assess the consistency of listings, severity, and scientific evidence ratings of DDIs involving the oral anticancer agents that were selected. The Spearman correlation test was used to assess the correlation of the severity ratings between the 2 compendia.

RESULTS: A total of 184 DDIs were identified. A DDI profile was created for 40 of these that met the predetermined criteria for clinically significant interactions. The comparative assessment showed inconsistency in DDI listings (15.2% of those identified were listed in DIF only and 46.7% were listed in Micromedex only), severity ratings (Spearman correlation coefficient 0.49), and scientific evidence ratings (disagreement 25.8%).

CONCLUSIONS: The discrepancies in DDI listing and rating systems between the compendia evaluated here reflect the need for more studies to standardize the definitions and classifications of DDIs.

Key Words: drug compendia, drug-drug interactions, drug information

Published Online, November 25, 2008. www.theannals.com, DOI 10.1345/aph.1L255

Drug-drug interaction (DDI) is an important issue among the cancer population. It is commonly observed in these patients, especially because they often receive multiple medications concurrently with complex chemotherapy regimens. It was shown previously that patients who are taking multiple medications for the treatment of comorbid illnesses experience an increased incidence of drug interactions.1,2 Other factors, such as age-related renal and/or hepatic insufficiency, can also affect drug metabolism, elimination, and clearance, causing elderly patients with cancer to become even more susceptible to DDI effects.3

Over the past few years, there has been a paradigm shift in cancer treatment from parenteral to oral drug administration,4 with many of the newly approved anticancer agents being administered orally. Oral anticancer treatment offers patients greater convenience and flexibility for timing and location of drug administration, reduced use of healthcare resources, and most importantly, a better quality of life compared with parenteral anticancer therapy. Despite these benefits, potential hazards of oral treatment include interactions with other prescription and nonprescription medications as well as complementary therapies. Several risk factors predispose patients with cancer who are receiving oral anticancer agents to develop adverse DDIs; these include malabsorption, malnutrition, disease states, and pharmacokinetic differences in individual patients.5

One way to prevent DDI mishaps is early recognition of the interaction, particularly in patients who are receiving concomitant oral anticancer and nonanticancer agents. Regarding early recognition, clinicians can use drug compendia to research DDI information. Currently, a number of commercial DDI databases are available; compendia such as Drug Information Facts (DIF) and Micromedex are commonly used resources that can provide detailed DDI information including onset, severity, scientific evidence, pharmacologic effects, mechanisms of action, and management. Although references can be helpful in identifying drug interactions, studies have shown that major conflicts exist among drug compendia on drug interaction information, particularly with regard to information such as severity and evidence ratings.6-8

The primary goal of this study was to capture clinically important DDI information based on literature reviews and drug interaction compendia. With these clinically important DDIs identified, structured, comprehensive, and up-to-date DDI profiles were created. The secondary goal of this study was to evaluate the consistencies of the drug information resources by making a comparative assessment of the level of consistency between 2 compendia on DDI listings and the ratings of severity and scientific evidence, with specific focus on interactions involving oral anti-cancer agents and nonanticancer agents.


   Methods
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SELECTION OF DRUG-DRUG INTERACTION CANDIDATES
DDI candidates are the oral anticancer agents of interest in this study. A total of 32 of these drugs were identified and are collated in Table 1. Selection of oral anticancer agents was based on drugs available and most commonly used at National Cancer Centre Singapore.


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  		Table 1. Oral Anticancer Agents Evaluated

 

DRUG-DRUG INTERACTION PROFILING AND LITERATURE SEARCHES
DIF 20089 and Micromedex DRUGDEX database10 (updated October 2007) were the 2 main compendia used to create the DDI profiles involving nonanticancer agents and the selected oral anticancer agents. There also are clinically relevant drug-herb and drug-food interactions with the oral anticancer agents reviewed here; they are beyond the scope of this study. DIF and Micromedex use different terminologies and rating systems to classify the clinical significance of DDIs. The severity of DDIs in DIF is categorized into 3 categories (major, moderate, minor) and the level of scientific evidence is divided into 5 categories (established, probable, suspected, possible, unlikely). Micromedex classifies the severity of DDIs into 5 categories (contraindicated, major, moderate, minor, unknown) and the level of scientific evidence into 6 categories (excellent, good, fair, poor, unlikely, unknown).9,10

In the compilation of DDI profiles, only the interactions listed in both compendia and considered clinically significant were included. A clinically significant DDI is defined in this study as having (1) a severity rating of major or moderate and a scientific evidence rating of established, probable, or suspected in DIF, and (2) a severity rating of contraindicated, major, or moderate and a scientific evidence rating of excellent, good, or fair in Micromedex.

Considering that there might be DDI information that is not reported in either compendium, literature searches using PubMed MEDLINE were carried out between November 2007 and January 2008 to update the data in the DDI profiles. Key words used during the literature search included antineoplastic agents, anticancer agents, oral antineoplastic agents, oral anticancer agents, drug interactions, drug-drug interactions, and adverse effects. In addition to the listed key words, drug names (generic and brand names) of the DDI candidates were also used in the search.

To ensure consistency of the DDI profiles, all of the interacting agents were classified into drug classes based on either their mechanisms of action, structures, or therapeutic effects. A total of 18 drug classes were used in the profiles.

COMPARATIVE ASSESSMENT OF THE COMPENDIA
DIF 2008 and the Micromedex DRUGDEX database were compared to assess the consistency of listings, severity, and scientific evidence ratings of the DDIs. In this analysis, only DDIs listed in both compendia were included. Each DDI listed in either compendium was checked against the other to determine whether there was a discrepancy between them. The correlation of the severity rating systems used in DIF and Micromedex was assessed using the Spearman rank correlation test, which was performed using SPSS 15.0 for Windows (SPSS, Chicago, IL).


   Results
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DRUG-DRUG INTERACTION PROFILING
Of the 32 oral anticancer drugs identified, only 25 had DDIs documented in either DIF or Micromedex. Eighteen (56.3%) candidates were listed in both compendia, and 7 (21.9%) were not found in either compendium (ie, anastrozole, letrozole, chlorambucil, lomustine, temozolomide, exemestane, uracil-tegafur). MEDLINE searches identified DDIs for chlorambucil, lomustine, and exemestane. As a result, a total of 184 DDI pairs were identified for the 28 drugs.

Among the 184 DDIs identified, certain nonanticancer drugs were commonly cited as an interacting agent with the 28 oral anticancer drugs. The nonanticancer agents most frequently involved were anticoagulants (53.8%), followed by hydantoins (42.8%), rifamycins (35.7%), and antifungals (32.1%).

In the selection of DDIs for profiling, individual drugs with a severity or scientific rating different from that of other drugs in the same class were considered different DDIs. Forty DDIs met the predetermined inclusion criteria as clinically significant, and a profile was developed for each of these combinations (Table 2).11-159


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  		Table 2. Profiles of Clinically Significant Drug-Drug Interactions

 

AGREEMENT BETWEEN DIF AND MICROMEDEX
Among the 184 DDIs, only 31.0% were listed in both compendia; 46.7% were listed only in Micromedex and 15.2% were listed only in DIF. For the assessment of rating systems, the severity and scientific evidence ratings used in both DIF and Micromedex were grouped into 3 categories: major, moderate, and minor for DIF and contraindicated/major, moderate, and minor for Micromedex. Likewise, scientific evidence ratings for DIF were classified as established, probable/suspected/possible, and unlikely, and Micromedex ratings were classified as excellent, good/fair/poor, and unlikely. This was done due to the differences in the definitions of these terminologies in the 2 compendia.

Similar to drug profiling, in the ratings comparison, individual drugs were considered as individual DDIs if the drugs had different severity and scientific evidence ratings from others in the same class. As shown in Table 3, the disagreement between DIF and Micromedex was 25.7% in both severity and scientific evidence ratings. The Spearman rank correlation test result suggested a medium correlation between DIF and Micromedex on the severity rating (rs = 0.49; p < 0.001).


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  		Table 3. Classification of Drug-Drug Interactions Based on Severity and Scientific Evidence in DIF and Micromedexa

 


   Discussion
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As oral anticancer agents are gaining wide acceptance for the treatment of malignancy, they are often used in conjunction with nonanticancer medications. As a result of this, prominent issues such as DDIs can surface and pose new challenges to practitioners.160 Healthcare professionals need to increase their vigilance and improve their recognition of potential DDIs that can lead to clinically significant adverse events.

Through primary and tertiary references, we successfully identified 184 DDI combinations, with 40 classified as clinically significant. The highest number of interactions was observed with anticoagulants and hydantoins, which is consistent with findings of similar studies that investigated the prevalence of DDIs with all anticancer agents.2 Our study has shown that a similar observation holds true when we focus on DDIs that involve the oral drugs.

The DDI profiles created here (Table 2) can be useful in many ways to increase the awareness of DDIs related to oral anticancer drugs. These profiles can be printed on a pocket-size pamphlet and distributed to oncologists and pharmacists as handy references or can be incorporated into computerized physician order entry systems as reminders to prescribers. As suggested in other studies, oncologists can work with pharmacists to develop electronic tools to improve the identification of DDIs.5 In addition, research is needed to examine how frequently these drug combinations are being prescribed and whether the DDIs actually cause harm to patients.

Our study has also identified discrepancies between DIF and Micromedex with regard to DDI listings and rating systems for severity and scientific evidence of DDIs between oral anticancer agents and drugs from other classes. Although this study was limited to only 28 oral anticancer agents, the results are consistent with those from another study in which a comparative assessment of 4 interaction compendia (Vidal, DIF, Micromedex DrugReax, British National Formulary) was done.8 In that study, major interactions for a list of 50 non-oncology drugs were assessed and the investigators noted a weak correlation between DIF and Micromedex on severity and scientific evidence ratings. The Spearman correlation coefficients found in that study for DIF and Micromedex were 0.55 and 0.43, respectively.

We believe that our study is the first to evaluate DDI information from different references on oral anticancer agents. Despite the generally modest overall agreement between the 2 compendia compared, it is noteworthy that the references tended to agree on what does not constitute minor severity and unlikely scientific evidence, with few (<5%) and none of the DDIs rated as minor and unlikely by either compendium, respectively. Rather, the majority of the DDIs are considered as major or moderate under the severity ratings of both compendia. As anticancer drugs are considered to be high-alert medications and DDIs may lead to significant adverse outcomes, it is not surprising that only 3% of the interactions are classified as being of minor severity in both compendia. In addition, none of the DDIs listed in both compendia was classified as unlikely, which indicates that some scientific evidence, although it may be limited, could be found for each interaction.

The discrepancies in DDI listings between the compendia seem to suggest that either DIF is underreporting or Micromedex is overreporting DDIs. One reason could be the lag time between data collection and publication of DIF, as DDIs are continually identified in controlled trials and published in journals. The inability to include these more recent and updated interactions could result in many DDIs being excluded from the 2008 published DIF. Micromedex, on the other hand, is an online database and it is updated every 3 months, which results in a shorter lag time between updating and publishing the data. Therefore, Micromedex could have included more recent DDIs involving oral anticancer agents and nonanticancer drugs that were not reported in DIF 2008. It is advisable that healthcare professionals consult more than just one DDI information reference source to ensure that it is indeed safe to use certain drugs concomitantly.

Several factors could have contributed to the discrepancies observed in the rating systems of severity and scientific evidence between DIF and Micromedex. First, both compendia might have obtained information from different sources, such as journal articles in languages other than English, reports not published by drug companies, reports collected from postmarketing surveillance, and product package inserts.8 Depending on which resource is used, the DDI information provided can be different. For example, the severity ratings for a DDI effect may be rated as less severe in the package insert compared with that noted in postmarketing surveillance reports, or vice versa. This is because the severity of DDI effects seen in subjects in randomized controlled trials may not be completely representative of the general population, compared with postmarketing surveillance studies, where a larger and more diverse segment of the general population is involved.161,162 Second, both compendia might have extrapolated the DDI of one drug to other drugs within the same class, based on different assumptions.8 Third, there is no standardized method of classifying DDIs and assessing their clinical relevance.8 Inconsistent definitions of terminologies in both compendia could also have contributed to the discrepancies observed in severity and scientific evidence ratings. For example, the DDIs that were rated as contraindicated in Micromedex could have been rated as major in DIF, since DIF does not use the term contraindicated in its severity ratings, while Micromedex does.

This lack of consistency can lead to several clinical implications. For instance, this may pose a problem for healthcare professionals who need to seek information about a particular DDI and, in the process, become confused upon their realization that there is disagreement in the information provided by different compendia. Similar DDI information should be reported in compendia so that healthcare professionals can work more efficiently, without the need to search for additional information to clarify the discrepancies observed. This can help prevent healthcare professionals from wasting precious time that could be spent with patients. In addition, the discrepancy in DDI listings can result in potential interactions occurring in patients if the DDI is not identified in the particular compendium used by healthcare professionals. Such discrepancies may be detrimental, especially in oncology settings, because DDIs involving oral anticancer agents may result in increased risk of drug toxicities. Therefore, it is very important to solve the problem of inconsistency on DDI listings and severity and scientific evidence rating systems among compendia.

Several studies attempted to propose criteria that are more user-friendly to identify and classify DDIs. Hansten et al.163 proposed that additional criteria should be used instead of only severity and scientific evidence ratings, which were deemed to be inadequate and too limited to classify DDIs. These proposed criteria include biological plausibility, the probable frequency of concomitant use of the 2 drugs in the general population, and the existence of warnings in the product package inserts. Malone et al.164 developed a 16-item instrument that aims to better define DDIs. The instrument includes 3 items about evidence supporting the DDI, 4 items about its severity, 5 items about its probability, and 4 items about the probability of coadministration of the interacting drugs. More recently, Horn et al.165 developed a drug interaction probability scale to evaluate drug interaction causation with an aim to assist practitioners in the assessment of drug interaction-induced adverse outcomes.

Our study has limitations. Although the drug profiles were supplemented with references from the primary literature, only 2 drug compendia were used to compile the profiles. We also limited our search to articles that were published in the English language. Furthermore, we used the 2008 bound edition of DIF rather than the loose-leaf version, which provides periodic updates. Although the results could have been slightly different if the loose-leaf version had been used, unfortunately, it was unavailable to us when the study was conducted. However, the most updated versions of both Micromedex and DIF (bound) were used to develop the drug profiles, ensuring that the latest information at that time was provided.

A standard evaluation tool should be developed and used to evaluate DDI inclusion and rating systems in compendia commonly used for DDI information to minimize any discrepancies. An expert panel comprising healthcare professionals such as oncologists, clinical pharmacists, and/or DDI experts can also play a role in DDI identification. If this expert panel can be dedicated solely to identifying DDIs, a specific computerized database system can be created for use with a standard evaluation tool. This database can then be updated frequently and made available to all healthcare institutions. More studies should be conducted to ascertain the best method for standardization of information among DDI information sources so that the variability in clinical practice and difficulty in evidence-based medicine practice among healthcare professionals can be minimized. Further studies may also look for a better way to define the different categories of severity and scientific evidence ratings of DDIs. They can also determine parameters (other than severity and scientific evidence ratings) that can be used to accurately classify the severity of DDIs.


   Conclusions
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 Discussion
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References
 
Further studies should be conducted to create a standard evaluation tool or selection criteria to standardize the definitions and classifications of DDIs among compendia commonly used to identify DDIs. As more oral anticancer agents are introduced into patients' therapy, clinically important DDIs should be prevented or identified for the benefit of better patient care and medication safety in this population.


   Footnotes
 
The Department of Pharmacy, National University of Singapore, provided Final Year Project funding for this project.

This work was previously presented at the 2008 Singapore General Hospital 17th Annual Scientific Meeting.


   References
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