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Critical Reviews in Clinical Laboratory Sciences

ISSN: 1040-8363 (Print) 1549-781X (Online) Journal homepage: http://www.tandfonline.com/loi/ilab20

FDA-approved drugs that interfere with laboratory


tests: A systematic search of U.S. drug labels

Hui Yao, Elizabeth R. Rayburn, Qiang Shi, Liang Gao, Wenjie Hu & Haibo Li

To cite this article: Hui Yao, Elizabeth R. Rayburn, Qiang Shi, Liang Gao, Wenjie Hu &
Haibo Li (2016): FDA-approved drugs that interfere with laboratory tests: A systematic
search of U.S. drug labels, Critical Reviews in Clinical Laboratory Sciences, DOI:
10.1080/10408363.2016.1191425

To link to this article: http://dx.doi.org/10.1080/10408363.2016.1191425

Accepted author version posted online: 18


May 2016.
Published online: 18 May 2016.

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Download by: [University of Nebraska, Lincoln] Date: 20 May 2016, At: 03:23
FDA-approved drugs that interfere with laboratory tests: A systematic search of

U.S. drug labels

Hui Yao1*, Elizabeth R. Rayburn2*, Qiang Shi3, Liang Gao1, Wenjie Hu1, Haibo Li1

1
Department of Clinical Laboratory Medicine, Nantong Maternity and Child Health

Hospital, Nantong, China


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2
CLIA Laboratory Director (various laboratories), Birmingham, AL, USA

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3
Division of Systems Biology, National Center for Toxicological Research, U.S. Food

and Drug Administration, Jefferson, AR, USA


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*
These authors contributed equally to the manuscript
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Address correspondence to: Haibo Li, Ph.D., Department of Reproductive Medicine,

Nantong Maternity and Child Health Hospital, Nantong, China. Email

ntlihaibo2015@163.com
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Keywords: Drug-related laboratory test interference (DLTI), prescription drugs, FDA

labels, DailyMed

Referees Adel Ismail, Consultant in Clinical Biochemistry and Chemical


Endocrinology (retired), Tanglewood, Chevet Lane, Wakefield, West Yorkshire, UK;
Dr. Theo Rispens, Sanquin Research, Amsterdam, The Netherlands; Dr. Daniel
Amsterdam, Professor, Departments of Microbiology, Pathology, and Medicine,
School of Medicine, University at Buffalo, Buffalo, NY, USA.
Received 22 December 2015
Revised 08 May 2016
Accepted 16 May 2016
Published online

Abbreviations and Glossary

AACC, American Association for Clinical Chemistry, a global organization that is

dedicated to improving the clinical laboratory sciences and promotes their application
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for healthcare

ACE, angiotensin-converting enzyme

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ALT, alanine transaminase

AST, aspartate transaminase TE


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ADME, absorption, distribution, metabolism and excretion

CBC, complete blood cell count, a common laboratory analysis performed to


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determine the numbers erythrocytes, leukocytes and thrombocytes, as well as the


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hemoglobin and hematocrit concentrations and mean corpuscular volume

DailyMed, a U.S.-sponsored online database of drug labels that is free to use


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DLTI, drug-related laboratory test interference or drug/laboratory test interactions, the

interference of xenobiotic substances with laboratory assays


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EMR, electronic medical records


FDA, U.S. Food and Drug Administration, the U.S. entity responsible for regulating

new foods and health-related products


IFCC, International Federation of Clinical Chemistry and Laboratory Medicine

IQCP, Individual Quality Control Plan


LDH, lactate dehydrogenase
OTC, over-the-counter, referring to health-related products that are sold to consumers

but have not been FDA-approved

PT/INR, prothrombin time/international normalized ratio

Abstract

Drug-related laboratory test interference or drug/laboratory test interactions (DLTI) is

a major source of laboratory errors. DLTI is of concern with regard to both the clinical
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diagnosis and the monitoring of patients. Although there have been numerous reports

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about specific drugs that interfere with laboratory tests, there has not been a recent

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review on the topic. We herein provide a review of the known DLTI of U.S.

FDA-approved drugs based on a systematic search of DailyMed, a website containing


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the labels of U.S. FDA-approved drugs. The labels for all human single-ingredient
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prescription drugs included in the database (1,368) were searched using stemmed
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keywords, and were manually reviewed for their relevance to DLTI. A total of 134

labels were positive, which indicated that the drug interferes with at least one clinical

laboratory test. Antibacterial agents, psychotropic drugs, and contrast media are the
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classes of drugs most likely to lead to DLTI. Urine was the clinical sample most
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frequently affected by DLTI. The FDA drug label is a source of information for

studies of DLTI, although information is still lacking for most drugs, and additional

improvements are needed for many of the existing records. Medical professionals,

clinicians and laboratory staff should keep these possible interactions in mind when

interpreting the results of laboratory tests, and should ensure that they obtain a
complete and accurate record of all drugs being used by patients in order to anticipate

potential DLTI. The development of a reporting system to address potential DLTI is

warranted.

Introduction

The reliance of modern medicine on laboratory testing

The fundamental task of a clinical laboratory is to provide accurate and precise


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results for the diagnosis of a disease, determination of its prognosis, indications of

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changes in a patient’s condition over time, information regarding the response to

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treatment, and/or evidence of patient compliance with the treatment. There are

approximately 4,000 different laboratory tests that have been developed, about a
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quarter of which have payment rates set in the Medicare Clinical Laboratory Fee
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Schedule (1). It has been estimated that 70% of the medical decisions made in the U.S.
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are based on the findings of clinical laboratory tests (2). Although this high percentage

includes decisions made based on imaging and pathology studies, more than two

billion dollars were reimbursed by Medicare in 2006 for just four clinical chemistry
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tests (complete blood count, complete CBC panel with differential WBC counts;
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comprehensive metabolic panel[albumin, blood urea nitrogen, calcium, CO2, chloride,

creatinine, glucose, potassium, sodium, total bilirubin, total protein, and liver enzyme

levels (AST, ALP, AST)]; thyroid stimulating hormone assay; and routine lipid panel

[total cholesterol, LDL, HDL, and triglycerides]: HCPCS# 85025, 80052, 84443, and

80061, respectively (3)). Given the increasing demand for individualized medicine by
patients, laboratory testing will likely play an increasingly important role in clinical

decision-making.

This increasing use of and reliance on laboratory testing has been due to and has

led to the development of a wide variety of technologies, ranging from simple test

strip/dipstick immunoassays to genetic sequencing and microarrays. As the

complexity of the tests (and their interpretation) and the number of samples being

tested increases, the potential risk of interference with these tests by commonly-used
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substances will increase. The purpose of this review is to provide an updated

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summary of the FDA-approved (FDA, U.S. Food and Drug Administration),

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single-ingredient drugs that can interfere with the performance, outcome or

interpretation of laboratory tests. We also discuss the existing reporting of these


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findings, and suggest ways to improve the identification and understanding of
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drug-related laboratory test interference (DLTI).


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The implications of drug-related laboratory test interference

Although new instruments and methods are constantly being developed to


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provide more accurate results with greater sensitivity, there is a margin of error for all
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laboratory tests, and the testing may be affected by a number of factors. One potential

source of error is the drugs that the patients are taking. Many drugs lead to spurious

results for clinical laboratory tests by interfering with the assays. If the fact that the

test results are incorrect is missed, this may mislead the medical staff and potentially

result in harm to patients. Such harm may result from a missed diagnosis, an incorrect
diagnosis, improper prognostic prediction, an incorrect evaluation of the response to

treatment, or an incorrect evaluation of a patient’s drug use or compliance with the

prescribed treatment. While the potential risk may be minimal in some cases and

possibly lead only to an additional test being performed, there is a chance for some

interference to lead to a lost opportunity for treatment or to treatment with an

inappropriate therapy that would potentially lead to morbidity or death.

Although the rates of DLTI are currently unclear, there have been some large
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studies performed to examine the rates for immunoassays because their use of

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antibodies is inherently associated with a risk of cross-reactivity with endogenous

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immunoglobulins and heterophilic antibodies. The reported rates of DLTI for

immunoassays ranged from 0.4-4.0% (4). Although a accuracy rate of 99.5% is


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considered to be good for most assays, this rate still means that there are thousands or
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even millions (depending on the assay) of inaccurate results obtained every year.
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Methods such as the precipitation of heterophilic antibodies prior to testing are being

developed to further decrease this rate (5), but these are not yet widely used and they

will add to the cost and complexity of these tests.


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There are numerous requirements for method development that are considered by
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the instrument and reagent manufacturers, government regulatory bodies, and

individual laboratories that have been implemented specifically to avoid the risk of

DLTI. The FDA has set forth recommendations for testing for interference during the

development of devices/instruments and new testing methods by manufacturers that

are largely based on the target analyte(s), the type of test, and the substance(s) being
tested (blood, urine, histology, etc.) (i.e., sections 513 and 515 of the FD&C Act; 21

U.S.C. 360c and 360e) (6). The findings of such testing are included in the user

manual or instructions for use of the instruments/reagents. These can provide useful

information to the laboratory staff, but are often not reflective of the actual conditions

in the laboratory. There may be a different spectrum of interference due to differences

in the instrument performance in the laboratory (e.g. effects of temperature and

humidity), differences in the patient population (e.g. different ethnicity, underlying


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diseases, seasonality or timing of the sample collection), and differences in the skill

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level of the laboratory staff. Ideally, interference testing should be performed by both

the instrument/reagent provider and by the end user.


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Most method validation protocols, especially for high-complexity testing, include
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steps to search for interference by several of the most commonly-used
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over-the-counter (OTC) and prescription drugs and drugs with structures that are
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similar to that of the target analyte. However, it is impossible for manufacturers and

laboratories developing methods to identify all potential sources of cross-reactivity or

drug-related interference during method validation. In addition, while validation is


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now required for all laboratory-developed tests, there are no detailed requirements for
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interference testing, only that the test be specific and precise (7). Thus, efforts must be

made to continue monitoring for interference and to record cases of suspected

interference as they arise, because not all can be identified or examined during the

initial method development and validation.


Existing knowledge about DLTI

Drugs can impact the results of laboratory tests in several ways. One is by

altering the pharmacology/ADME (absorption, distribution, metabolism and excretion)

of other drugs. Another is by altering the biological sample being tested (e.g.

hemolysis in blood). Some drugs also interfere directly with the test itself by reacting

with the test reagents. This review will focus on the latter two mechanisms of drug

interference with laboratory tests.


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Although there have been numerous reports about drug-related interference with

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laboratory tests, most of them have focused on individual drugs, methods, or

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instruments (8-14). There have been only a few reviews that have attempted to

provide an overall summary of the variety of data presented in these reports. The
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authority in the field has long been Dr. Donald Young, who published several reviews
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(including three in the 1970s and another in 1997) about the impact of drugs on
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laboratory tests (14a, 15-17). He additionally participated in the launch with the

American Association for Clinical Chemistry (AACC) of a large online database in

2004 that was based on several of his previously published books; this database is still
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active and includes detailed information about various DLTI (18). Although Dr.
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Young’s work laid the foundation, additional reviews and continuous reporting of

potential DLTI are needed.

Aims of this review

To our knowledge, no comprehensive profile of drug-related laboratory test


interference has been reported in more than a decade. Therefore, in the present review,

we provide an updated and comprehensive overview of the DLTI associated with

single-ingredient U.S. Food and Drug Administration (FDA)-approved drugs.

According to the updated guidelines issued by the U.S. FDA in October 2011, the

information about any known drug interference with clinical laboratory tests must be

briefly noted in the WARNINGS AND PRECAUTIONS section of the drug label (19).

In the present study, we reviewed and analyzed all of the FDA-approved human
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prescription drug labels deposited in DailyMed (https://dailymed.nlm.nih.gov

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[last accessed 15 May 2016), which contains more than 85% of all U.S. drug labels,

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and analyzed the information related to DLTI, including the drug classification,

laboratory assay classification, and the mechanism by which the drug interferes with
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the assay (if known).
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Methods

The inclusion and exclusion criteria for the drugs evaluated in the study

Nearly all U.S. drug labels are deposited in the federal DailyMed website. A list
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of drugs for subsequent study was developed based on a search of the DailyMed
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website performed on April 22, 2015. The recorded information included the product

name, product generic name, market category, route(s) of administration, dosage

form(s), and the last time the label was updated.

We examined only the drugs used for humans (drugs intended for animal use

were not considered). Only FDA-approved prescription drug labels were included for
review. Over-the-counter (OTC) drugs were excluded from the database because

DLTI-related information was generally not available in their labels. The drugs

containing multiple active ingredients were also excluded because this made it

difficult to evaluate the effects of a specific compound. When there were repeated

labels for the same drug from different companies, or when there were labels that had

been updated at different times, only the latest label was used for the subsequent

review.
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Searching with keywords

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The labels for all drugs included in the study were downloaded from DailyMed in

the PDF format. A hyperlink that linked the drug in the database to the PDF document
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was established to conveniently access the information. For every PDF document,
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stemmed keywords were used to search the label contents for relevant information;
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these keywords included “analy*”, “artifact*”, “assay”, “clinic*”, “determine*”,

“erro*”, “false”, “interfer*”, “interact*”, “lab*”, “spuriou*” and “test” to cover the

potentially useful information to the best extent possible. Every stemmed keyword
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represented several words potentially related to DLTI (e.g. “analy*” was used to find
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information related to “analyse(d)(s)” “analyze(d)(s)”, “analysis”, “analyte”, and

“analytical”).

The PDF documents were manually searched independently by two authors using

these keywords, and the described relevance to DLTI was copied and pasted into an

Excel database. If there were differences in the descriptions obtained by the two
authors, they were resolved by discussion with another author, and the group opinion

was used for the statistical analyses. Only the labels with a confirmed description

related to DLTI were included in the study, such as “High urine concentrations of

ampicillin may result in false-positive reactions when testing for the presence of

glucose in urine using the CLINITEST, Benedict’s Solution, or Fehling’s Solution.”, or

“Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction, causing

falsely low readings in serum cholesterol determinations.”


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Analysis of the findings

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For the drugs with positive findings in the FDA labels regarding interference with

laboratory tests, we performed further analyses. The positive drugs were classified by
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their applications according to the principle category in the US National Library of
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Medicine (http://druginfo.nlm.nih.gov/drugportal [last accessed 15 May 2016]). The


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anti-infective agents were defined as all agents targeting microbes other than bacteria

(e.g. antiviral, anti-fungal, anti-malarial, and anti-protozoal agents). Antidepressant,

anti-Parkinson and antipsychotic agents were all listed in the category of psychotropic
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drugs, because they result in changes in brain function and result in alterations in
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perception, mood, or consciousness. The cardiovascular agents included all drugs

indicated for problems with the circulatory system (e.g. anti-hypertensive drugs,

beta-blockers, antiarrhythmic drugs).


Results

The drugs included in this study

As of April 22, 2015, a total of 65,536 labels had been deposited in DailyMed. A

total of 29,145 labels were excluded for 24,859 OTC drugs that did not include

relevant information. Another 814 drug labels for drugs used only in animals and

11,199 labels for non-FDA-approved drugs were also excluded from further analysis.

A total of 22,724 human drug labels were kept after deleting the labels for
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medicinal foods, medical devices, dietary supplements, cosmetics, bulk ingredients,

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diagnostic kits, etc. For the drugs with multiple labels from different manufacturers,

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different effective doses, and/or different routes of administration and/or dosage forms,

only the latest label was used for the analysis. The final list of human
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single-ingredient prescription drugs included 1,368 drug labels, which were all
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examined for information about interference with laboratory tests.


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The profile of DLTI in the FDA-approved single-ingredient prescription drugs

The most prominent finding of this study was that only 12.35% (169/1,368) of the
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FDA labels for human single-ingredient prescription drugs provided explicit


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information related to DLTI. Among these, 134 labels clearly indicated that the drug

interferes with laboratory tests (shown in Table 1 (urine-based assays) and Table 2

(blood-based assays)), 31 labels indicated that the drug did not interfere with

laboratory tests, and only four labels noted that there was no information regarding

laboratory test interference for the drug. There is no information related to DLTI
available in the labels for most of the FDA-approved prescription drugs. This

indicates that studies of DLTI have been lacking for most drugs.

The drugs most likely to interfere with laboratory tests

Anti-bacterial agents. Based on the drug labels, anti-bacterial agents are the drugs

most likely to interfere with laboratory tests. Most of the reported interfering

anti-bacterial agents were cephalosporins, and the clinical laboratory tests most
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susceptible to interference by the cephalosporins were urine glucose and ketone tests.

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The administration of cephalosporins may result in a false positive reaction for

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glucose in the urine using the Clinitest® (Bayer, Ecatepec, Mexico), Benedict's

solution, or Fehling's solution. The Clinitest® reagent tablets and Benedict's and
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Fehling’s solutions contain blue copper (II) ions (Cu2+), which are reduced to copper
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(I) ions (Cu+) by sugars and reducing substances (20-22). These are precipitated as
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red copper (I) oxide, which is insoluble in water, and can be used to assess the level of

glucose/ketones in urine. Several cephalosporins also reduce the copper ions, leading

to false positive results. Fortunately, these three methods are seldom used in clinical
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laboratories today because of the development of newer methods and automated


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assays. In addition, almost all of the labels for these drugs recommend that glucose

testing should be based on enzymatic glucose oxidase or hexokinase reactions to

avoid false positive findings. However, Benedict's and Fehling's solutions may still be

used for glucose tests in some rapid test strips sold in pharmacies or supermarkets,

and consumers may not understand the implications of such DLTI. Of interest, many
cephalosporins also lead to false positive findings for the direct Coombs test (to detect

immune-mediated hemolytic anemia), findings which could potentially lead to an

incorrect diagnosis.

Some anti-bacterial agents can also interfere with the detection of the clotting

time. Both telavancin and daptomycin lead to falsely prolonged/elevated PT/INR

(prothrombin time/international normalized ratio) findings, which could lead to an

unnecessary and potentially dangerous decrease in the dose of anticoagulant being


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given. These agents appear to act via distinct mechanisms, with daptomycin

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interacting with the recombinant prothrombin reagent, and telavancin interacting with

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the surface of the phospholipids included in the test kits, and preventing the

coagulation complexes from assembling (23, 24).


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Psychotropic drugs The psychotropic drugs were found to be the second most likely
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agents to interfere with laboratory tests. These agents include antidepressants,

antidyskinesia agents and antipsychotic agents. The determination of whether a

patient is positive for a drug such as phencyclidine, amphetamine or benzodiazepines


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may be affected by treatment with other psychotropic drugs. This interference is


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logical, because the structures of phencyclidine, amphetamine, and benzodiazepines

drugs are similar to those of the other psychotropic drugs or their metabolites. This

potential for interference needs to be kept in mind by laboratory personnel and/or

clinicians (or by the agency performing employee drug testing), because it may lead

to incorrect conclusions regarding compliance.


Of note, these drugs also have some other forms of interference that occur via an

unknown mechanism. For example, some of these drugs have been reported to lead to

false positive results on pregnancy tests, and information is not available in the drug

label (or in the literature) to explain the reason for this interference. Most pregnancy

tests are carried out using immunoassays based on human chorionic gonadotropin

(HCG) and anti-HCG antibody binding (25). Theoretically, this is the most specific

assay method currently used in clinical laboratories, so it is difficult to explain why


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some psychotropic drugs would cause interference.

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Contrast media According to the FDA labels, contrast media are another major class

of drugs that interfere with laboratory tests. A medical contrast medium is a substance
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used to enhance the contrast of structures or fluids within the body during medical
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imaging. Organic iodine molecules are the most common type of contrast media used
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for enhancement in X-ray-based imaging methods, whereas gadolinium contrast

agents are typically used in magnetic resonance imaging. The iodinated contrast

media can cause inappropriate gel barrier formation in blood tubes, which affects the
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determination of protein levels in the blood using some methods (26). The
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interference of gadolinium contrast agents includes a negative bias in calcium

assessment with the ortho-cresolphthalein colorimetric assays, an occasional positive

bias using some arsenazo reagents, a negative bias in the measurement of

angiotensin-converting enzyme (ACE) and zinc (colorimetric assay), as well as a

positive bias in determinations of creatinine (Jaffe reaction), total iron binding


capacity (TIBC, ferrozine method), magnesium (calmagite reagent) and selenium

(mass spectrometry) (9). Since the elimination half-life of contract media is typically

less than 2 h, blood collection after this period should be recommended in patients

who have received contrast media for diagnostic purposes (9).

Although these classes include the largest numbers of drugs with an impact of

clinical laboratory tests, there are individual drugs across various classes that can

impact different tests.


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The clinical impact of the known DLTI

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The mechanisms by which drugs interfere with laboratory tests are diverse, as

illustrated by the above examples, but the most common mechanisms involve
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inhibiting enzymes (either in the patient or an enzyme used for the assay), the
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induction of fluorescence or coloration in a sample by the drug, an increase in sample


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turbidity, chemical cross-reactions, or competitive binding (to an enzyme, antibody or

other indicator). Most of the drugs interfere with laboratory tests by disturbing the

assays for the chemical components in the urine. Urine is the second most common
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sample used in the clinical laboratory, after serum and/or plasma. Urine is used
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whenever possible because it is convenient and minimally-invasive in terms of sample

collection. In addition, urine is particularly important for the screening of illegal drugs

and many hormone assays.

Although less common than interference with urine-based testing, interference

with blood-based testing (serum or plasma) may be more important in terms of the
clinical impact. This is because urine is usually used to screen for conditions that are

not immediately life-threatening (diabetes, pregnancy, hormone levels, drug use/abuse,

etc.), while blood is more often used for immediate decision-making regarding

potentially life-threatening conditions in the clinical setting (blood cell counts,

hemoglobin level, blood gases, liver enzyme levels, etc.). Thus, while it may be less

common, interference with blood sample-based testing is more concerning (and is

more likely to have a dire clinical impact) than interference with urine-based tests.
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The non-emergency nature of the urine testing allows for confirmation testing using

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another method or for repeated testing under different conditions. This may be part of

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the reason why there are more known/documented DLTI for urine than for blood,

although the methods used for urine testing (including, frequently, immunoassays) are
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also associated with a higher innate risk of interference.
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It is difficult to pinpoint which of the DLTI are the most important clinically. No
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specific interference has been reported for nine of the 10 most commonly prescribed

drugs (based on a 2010 report, these were hydrocodone, simvastatin, lisinopril,

levothyroxine, amlodipine besylate, omeprazole, azithromycin, metformin and


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hydrochlorothiazide (27)), while amoxicillin has been reported to affect glucose


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detection by the copper reduction assay. As noted in the section above, several other

relatively common anti-bacterial agents such as cefdinir, rifampin, telavancin

hydrochloride, doxycycline and erythromycin also interfere with laboratory tests. As

shown in Tables 1 and 2, cefdinir interferes with glucose detection via specific assays;

rifampin affects the detection of opiates, folate and vitamin B; telavancin


hydrochloride affects the detection of clotting and urine protein; and both doxycycline

and erythromycin interfere with the fluorescence assays used to detect catecholamines.

Since these drugs are also used relatively often, they have a high potential to cause

clinically-relevant DLTI.

Metronidazole and tinidazole (commonly-used anti-infective agents) both

interfere with various assays that employ reactions that result in free NADH, such as

some liver enzyme (aspartate transaminase (AST) and alanine transaminase (ALT)),
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triglyceride, lactate dehydrogenase (LDH) and hexokinase glucose assays, because

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these agents have absorbance peaks similar to NADH. Isoproterenol and labetalol

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(adrenergic agents) both interfere with laboratory tests, but have different activities.

Isoproterenol interferes with the detection of bilirubin, while labetalol affects the
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detection of fluorometric assays for catecholamines, normetanephrine and
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metanephrine, and thin-layer chromatography and radioenzymatic assays for


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amphetamines.

Although other methods of detection exist for most of these assays, laboratories

will often not have an alternative method available, and many forms of interference
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are not specifically considered by the laboratory staff. In addition, even if the
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discrepant finding is due to a DLTI recognized by the laboratory staff, patients may

fail to provide an accurate record of the medications they are taking, making it

impossible to conclude that the abnormal finding is truly due to DLTI. Thus, while the

reported percentages of most types of DLTI that have been examined in previous

studies have been low, the real rate may be much higher due to a lack of confirmation
of the effect and a lack of reporting.

The use of automated systems and electronic medical records to identify potential

DLTI

The large number of prescription drugs and the variety of assays performed,

especially in the hospital setting, can make it difficult for even experienced laboratory

personnel to keep track of the potential DLTI. Moreover, in some cases, patient
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samples are assayed by people who are not laboratory professionals or who have

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limited laboratory knowledge (particularly for waived testing). Therefore, it is

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important to understand which drugs interfere with laboratory tests, including their

mode of action and the extent of the impact, so that these personnel (and the clinicians
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they report to) fully understand the limitations of the tests (28-31).
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It was reported almost forty years ago that automatic notification of potential
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DLTI could help physicians better interpret test results and choose a better treatment

strategy. Although only 0.1% of treatments were changed based on the notification of

potential DLTI (per changes noted in the medical charts), this would result in
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treatment changes in a substantial number of patients given the total number of


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patients treated each year in the U.S; additionally, while only 0.1% of the recorded

treatment strategies were changed, the physicians in that study reported more frequent

changes to their selected treatment strategy based on the notification (which may not

have been recorded in the charts at the time) (32). There have also been reports of

other “reminder” systems that were used to warn clinicians and/or laboratory
personnel of potential DLTI based on the patient’s prescriptions (using pharmacy

records) and known DLTI (based on databases existing at the time) (33). Such

reminders can help to ensure that assay results are checked for accuracy in patients at

risk of DLTI prior to being used for clinical decision-making.

However, while the above system was found to be useful, patient records are

frequently incomplete or inaccurate. Moreover, even if the records are accurate, they

may not be transferred between clinics or institutions, or may not be received until
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after a course of treatment has begun. This is slowly changing because electronic

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medical records (EMR) must now be used by all public and private healthcare

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providers (in the U.S.) in order for them to receive full payments from Medicaid and

Medicare (beginning in 2015). This mandated use of EMR provides better


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opportunities to monitor for potential DLTI, because the use of electronic records
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permits both the easier transfer of records and the development of additional software
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add-ons that can identify discrepant results in the laboratory based on the patients’

prescriptions, health conditions and general clinical picture, even when new (as yet

unidentified) DLTI are present.


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Proactive monitoring for potential DLTI is also made possible by the fact that
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several related markers are often evaluated at the same time (i.e. lipid parameters,

parent drug and metabolite(s), glucose and HbA1c, etc.). Since the levels of these

various markers are predictably related, a software program can be developed to alert

laboratorians and/or clinicians of potential DLTI if the relationship between known

markers is abnormal. For example, an elevated glucose level (blood or urine),


particularly if noted on more than one occasion, but without a concomitant increase in

the HbA1c, may indicate that part of the testing was affected and raise a flag that there

may have been DLTI.

Shortcomings of the FDA labels

Although the FDA drug labels present in DailyMed provided the most

comprehensive free source of information about DLTI, when we reviewed the drugs
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labels we found some shortcomings in that the information provided related to DLTI

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was insufficient or confusing. Some labels pointed out only that the drug or a specific

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dose of the drug did not interfere with a specific assay. This is not enough information

for the physicians and laboratory staff to assess the profile of DLTI for a drug.
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Guidance for some specific assays is provided in a few labels. For example, the

information included with naltrexone hydrochloride tablets indicates that “Naltrexone


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does not interfere with thin-layer, gas-liquid, and high pressure liquid

chromatographic methods which may be used for the separation and detection of

morphine, methadone or quinine in the urine. Naltrexone may or may not interfere
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with enzymatic methods for the detection of opioids depending on the specificity of the
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test. Please consult the test manufacturer for specific details”. Similarly, the label for

flucytosine capsules indicates that “Measurement of serum creatinine levels should be

determined by the Jaffé reaction, since Ancobon does not interfere with the

determination of creatinine values by this method. Most automated equipment for

measurement of creatinine makes use of the Jaffé reaction.” The information for
gadopentetate dimeglumine injection notes that “MAGNEVIST Injection does not

interfere with serum and plasma calcium measurements determined by colorimetric

assays.” The inclusion of this type of information is useful and should be encouraged.

According to the current FDA guidelines for drug labels (34), the

clearly-documented drug interference with clinical laboratory tests must be presented

in the drugs labels. Although this is helpful and represents a good start to

understanding DLTI, more proactive monitoring for interference is needed. While


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some interference may qualify as an adverse event and result in its being reported (e.g.

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if it leads to significant morbidity or death), most cases of DLTI or suspected DLTI go

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unreported. DLTI may not be reported for various reasons, including the fact that it is

often difficult in clinical practice to attribute altered test results to a particular drug,
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especially in patients receiving several drugs. In addition, the statements in the drug

labels about reported DLTI are generally vague – they only indicate the potential for
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AC

interference and sometimes the qualitative result (increase or decrease in the analyte).

The inclusion of specific findings (i.e., the concentration of a drug leading to a mean

Y% change in the target analyte) would be helpful. However, individual laboratory


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confirmation would likely still be necessary, since differences in the testing conditions,
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the skill level of the staff, and patient populations may lead to differences compared to

those found by the manufacturer or FDA.

Limitations of this review

Although this is a relatively comprehensive review on single-agent


FDA-approved drugs, no multi-ingredient drugs, over-the-counter medications,

supplements, herbal/alternative medicines or “nutraceuticals” (food-derived products

with health benefits) are included. These comprise a large number of chemical entities

that may also affect the results of laboratory tests. However, because there are so

many of these agents, and a paucity of consistent literature on the DLTI of these

agents, their effects are beyond the scope of this review.

Another limitation is that even within the DailyMed database (where


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manufacturers are required to provide information about DLTI), only about 12% of

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the agents actually had specific information available about DLTI (present, absent or

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unknown/untested). In addition, some of these labels were not sufficiently detailed.

Thus, there may be other types of interference (perhaps even by commonly-prescribed


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drugs) that are currently unknown.
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Additionally, a general limitation associated with evaluating DLTI is that it is


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difficult to gauge the clinical impact of the interference. For example, the outcome of

the test interference may be deleterious but not fatal (e.g. job dismissal due to a false

positive workplace drug test); fatal (e.g. death following a change in warfarin
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treatment based on a falsely elevated INR; or harmless (treatment was not changed
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because the parameter affected was only one of a set of parameters used to assess a

patient’s status). Moreover, additional testing (using a different assay, confirmation

testing, or testing of a new sample) may lead to correction of a spurious result without

any change to treatment being made based on the preliminary result.


Discussion and perspective

Increasing the awareness of DLTI

DLTI has been gaining increasing interest in the clinical setting and during the

drug development process. As mentioned above, the updated guidelines issued by the

FDA in October 2011 (Warnings and Precautions, Contraindications, and Boxed

Warning Sections of Labeling for Human Prescription Drug and Biological Products

— Content and Format, §201.57(c)(6)(iv)), indicate that information on any known


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drug interference with clinical laboratory tests must be briefly noted in the

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WARNINGS AND PRECAUTIONS section (34). The presence of drug/laboratory

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test interference means that the laboratory test results may be inaccurate because the

drug interferes with the assay (e.g., a false positive or negative test result is obtained
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that does not accurately reflect the quantity, presence, or absence of the analyzed
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substance). It should be kept in mind that this does not refer to a situation in which the
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test result is accurate, but the findings are outside the normal range because of the

physiological effects caused by the drug or its metabolites.

Although known DLTI must be included in the prescription drug labels according
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to FDA regulations, there are currently no FDA guidelines for industry regarding
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DLTI studies during drug development. The International Federation of Clinical

Chemistry and Laboratory Medicine (IFCC) issued a proposal for the study of the

effects of drugs on laboratory assays in 1984, and most of the studies published about

DLTI have been designed and carried out according to this proposal or modifications

of the original proposal (35-38). Some DLTI are uncovered during development or
early post-marketing surveillance, and are subsequently reported in the drug label. As

the regulator of drug approval, the FDA should issue official updated guidelines for

DLTI studies in the near future, at least for the most commonly-performed tests.

The role of the instrument and reagent manufacturers

As noted above, the validation protocols for most instruments, at least those used

for high-complexity testing, already take into account potential interference by many
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commonly used xenobiotics and substances normally present in the body, and thus

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help to identify DLTI. Nevertheless, it is not practical for these manufacturers to

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identify every possible DLTI. Thus, systems for reporting potential DLTI need to be

developed for new analytical instruments and methods.


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The instrument and reagent manufacturers and method developers may represent the

ideal “first-line” for detecting potential DLTI. They have extensive knowledge about
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AC

the reagents being used, including proprietary information that may not be available

to others but that might help to predict interactions. The current FDA

recommendations regarding testing for DLTI (34) and established ISO/TC212


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guidelines
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(http://www.iso.org/iso/home/store/catalogue_tc/catalogue_tc_browse.htm?commid=

54916&published=on&includesc=true [last accessed 15 May 2016]) can serve as a

starting point for the testing. The drawback to relying on the instrument and reagent

providers to detect DLTI is that the testing will be performed under ideal conditions,

with optimally maintained instruments and highly skilled staff, that do not always
reflect the actual conditions in the clinical laboratory.

The possibility of implementation of DLTI studies during clinical trials

It may be possible to implement a form of standardized evaluations for potential

DLTI during clinical trials. Clinical trials have strict inclusion and exclusion criteria

that provide relatively well-characterized populations, include close monitoring of

patients (with inpatient monitoring in some cases), and have relatively high rates of
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patient compliance with treatment. Although adding additional analyses will further

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increase the already high costs of clinical trials, standard laboratory panels are

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regularly run in patients participating in clinical trials, especially during the initial

safety assessments. All of these factors make it easier to monitor the new drug for
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potential DLTI, especially for interactions with common laboratory tests or tests
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specific to the target population.


AC

DLTI studies during post-marketing surveillance and in daily clinical practice

Another possibility would be to identify DLTI as part of the post-marketing


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surveillance. It might be useful for the FDA to start a system for the voluntary
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reporting of DLTI, similar to the current systems for reporting drug- and

device-related adverse events. Although some DLTI may fit under the current systems,

it is often unclear whether a spurious test result is truly being caused by the drug or

whether other factors may be involved. Thus, the reporting mechanism would ideally

allow for online submission of suspected DLTI by laboratory staff, physicians or other
medical personnel. Many laboratory technicians have suspicions about specific DLTI,

but do not report them because they are non-life-threatening and have not been

conclusively confirmed to be the sole cause of the spurious finding. There would

likely be an influx of suspected DLTI reports following the introduction of a new drug;

these would help to narrow down the tests potentially impacted by that drug, and the

accumulation of data in such a system would identify drugs that should be assessed

for specific DLTI by the FDA or contract laboratories.


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In addition to the FDA, other agencies and regulatory bodies could also develop

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strategies to address DLTI. For example, the Clinical Laboratory Improvement Act

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(regulations enforced by the Centers for Medicare and Medicaid Services) provides

regulatory standards for clinical laboratory testing. Future amendments should


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emphasize the importance of DLTI, and training materials should be developed for
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physicians, laboratory directors, and testing personnel to help them recognize


AC

potential sources of error related to DLTI. This might fit well under the Individual

Quality Control Plan (IQCP) for each lab. Similarly, the Substance Abuse and Mental

Health Services Administration oversees laboratories that perform forensic drug


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testing for federally-regulated programs and industries. Although some potential DLTI
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for illicit drug testing are known (such as bupropion hydrochloride giving positive

findings for amphetamines in some immunoassays (39)), large-scale prospective

tracking using a reporting system to track unexpected results/cases of unexpected

non-compliance would help to identify potential DLTI that can be confirmed by

experimental studies.
In general, there should be a “call to arms” made by the U.S. (and other)

government agencies to ensure that all physicians and laboratory staff understand the

potential risk of DLTI and make informed decisions regarding patient care based on

this knowledge. With the increasing use of EMR worldwide, software manufacturers

should also strive to help identify potential DLTI based on discrepant results between

the patient’s history or clinical picture or among markers with a known relationship,

and to provide automated notification of the risks of such DLTI.


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In the clinical setting, the recording of DLTI and suspected DLTI will require

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detailed and accurate history-taking, as well as improved transfer of medical records

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between institutions. Patient education regarding the importance of a full and accurate

picture of their use of prescription and other drugs (legal and illegal,
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physician-prescribed and OTC) is needed, along with physician and staff efforts to
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ensure that such information has been obtained from all patients.
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Of note, patients frequently take more than one prescription drug, or take

prescription drugs along with OTC products, herbal medications, “nutraceuticals”

and/or supplements. The incidence of clinical laboratory test interference by the drugs
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in these polypharmacy patients is expected to be higher than the incidence when the
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drugs are used individually. A previous study assessed the interference of various

drugs on laboratory tests in 100 outpatients; the percentage of tests affected by

interference was 7% when the patient was taking one drug, 16.7% when the patient

was taking two drugs, 66.7% when the patient was taking three or four drugs, and 100%

when the patient was taking five drugs (40). This is a challenge for drug developers,
instrument manufacturers and clinical laboratory scientists, and collaborative studies

of DLTI for patients receiving multiple drugs or OTC products are needed. The use of

software-based automatic monitoring of test results (including changes in results

compared to those obtained before the drug was taken) will be particularly helpful in

identifying potential DLTI, as well as analytical interference due to OTC medications

and supplements (provided they are reported by the patient).


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Existing databases about DLTI

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A few online databases have been set up to contain information about DLTI. The

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largest of these are the DailyMed website used in this review, the AACC Effects on

Clinical Laboratory Tests initially developed in collaboration with Dr. Young


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(mentioned earlier; 18); and the First Databank (FDB) MedKnowledge Clinical
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Modules, Drug-Lab Interference Module (41). Databases in other countries that report
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similar information have also been established. These databases can provide useful

information to physicians, laboratory directors and other clinical staff regarding

potential DLTI. While the formats differ, they all allow searches to be performed for
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DLTI related to specific drugs. DailyMed is currently the only free database.
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To our knowledge, no databases are currently able to be updated by anyone other

than those managing the database. This allowa the accuracy of the data regarding

DLTI to be preserved, but it would be useful for a new database to be developed to

allow the reporting of suspected DLTI by laboratory personnel and clinicians. Several

groups have proposed such databases, including Grönroos et al. (42), but none of
these has become widely used. The rapid changes in technology are likely responsible

for the failure of some of these systems. Given the costs and logistical issues, it will

probably require a federal government or a large organization (such as the World

Health Organization) to fund and manage such a database.

In order to make the database useful, it will need to be free, easily and rapidly

searchable, and ideally allow input from users. A crowd-sourced database in the vein

of Wikipedia might be useful by allowing users who choose to register to add new
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content while restricting the ability to change findings that have already been

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substantiated. Additional users could upload data that supports or refutes a putative

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DLTI. This type of reporting would suggest potential DLTI that should be examined

by researchers (or regulatory agencies) that might otherwise not be considered.


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Future directions and recommendations


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The FDA label currently provides the best source of free data about DLTI, but it

has limitations. As noted above, the majority of the drug labels do not currently

contain specific information about DLTI, largely because none exists. Moreover,
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much of the information that is included is not sufficiently detailed to inform


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clinicians and laboratory staff. This can be remedied by implementing required testing

for DLTI for the most commonly-performed laboratory tests by the instrument and

reagent manufacturers/providers, during clinical trials and as part of early

post-marketing surveillance, as well as by using automated software systems. The

ability to crowd-source data regarding suspected DLTI would also likely accelerate
research on the topic.

Although we have provided a comprehensive review of the single-agent

FDA-approved drugs in the DailyMed database and DLTI in general, we have barely

scratched the surface. The use of multiple prescription drugs, OTC drugs, herbal

products, etc. may also lead to analytical interference, as may prescription drugs

containing more than one active ingredient. There are also many foods that lead to

spurious test results. There is currently little information available about the impact of
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most of these substances, although some reports have been published in the literature

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(43, 44). The publication of standard methods for evaluating DLTI during method

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development, in clinical trials and early post-marketing surveillance, the development

of a large-scale database to list and update DLTI, increased assessment and reporting
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of DLTI in the clinical setting, and automated notification (perhaps implemented in
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the EMR) of discrepant laboratory results are all necessary steps that should be taken
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as soon as possible to limit the clinical impact of DLTI.

Summary/conclusion
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The most significant finding of the present study is that antibacterial and
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psychotropic agents and contrast media are the most likely drugs to cause DLTI.

These drugs also account for the majority of the agents used in hospitals and clinics.

Therefore, clinicians should pay special attention when making a diagnosis or

defining a patient’s status based on assay results in patients receiving these classes of

drugs. It also emphasizes the need for a precise and detailed history-taking to ensure
that patients disclose all drugs (prescription and OTC) and supplements (vitamins,

minerals, herbal supplements, nutraceuticals, etc.) that they are using because the

drugs may affect the outcome of laboratory tests.

The information about DLTI should be transmitted and widely disseminated to

clinical laboratories to ensure that all are informed about potential issues. At the same

time, the laboratory staff should be cautious when explaining the assay results for

patients who have taken these drugs. An alternate assay method or reagent that will
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not be affected by the specific drug should be used to obtain more accurate results

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whenever possible. In addition, the inclusion of automated notifications regarding

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discrepant laboratory findings (where the results do not agree with the clinical picture

or patient history, or where related markers do not show their usual relationship)
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would help to alert laboratory staff and physicians of possible DLTI.
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In summary, this is the first review offering information regarding the DLTI
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described in the labels of FDA-approved drugs. This information should be useful for

the pharmaceutical industry to consider during drug development and for government

regulatory agencies intent on revising industry guidelines. More importantly, it may


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serve as a reference for physicians and clinical laboratory staff to obtain better test
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results for clinical diagnostics and monitoring.

Acknowledgement

Dr. Haibo Li was supported in part by the International Cooperation and Exchanges

(2012) Program of the Department of Health in Jiangsu Province, China


Declaration of Interest Statement

The authors declare that they have no potential conflicts of interest with regard to this

manuscript.

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Table 1. FDA-approved single-ingredient drugs that affect urine-based assays
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
Aminosalicylic acid Anti-bacterial Ketones, bilirubin, ND ND
agent urobilinogen or
porphobilinogen

Amoxicillin Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Ampicillin Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Ampicillin Anti-bacterial Glucose False Interferes with the copper


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trihydrate agent positive/elevated reduction assay

Bupropion Psychotropic drug Amphetamines False Interferes with screening


hydrobromide positive/elevated immunoassay

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Bupropion Psychotropic drug Amphetamines False Interferes with screening
hydrochloride positive/elevated immunoassay

Buspirone
hydrochloride

Captopril
Central
system agent
nervous

Cardiovascular
Metanephrine
catecholamines

Acetone
and False

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positive/elevated

False
ND

ND
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agent positive/elevated

Carbamazepine Analgesic Pregnancy tests* ND ND

Carbidopa Psychotropic drug Ketone bodies False ND


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positive/elevated

Glucose False-negative Interferes with glucose-oxidase


AC

methods

Cefaclor Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Cefazolin Anti-bacterial Glucose False Interferes with the copper


ST

agent positive/elevated reduction assay

Cefdinir Anti-bacterial Susceptibility results for False ND


monohydrate agent citrobacter, providencia, positive/elevated
JU

and enterobacter spp.*

Ketones False Interferes with tests using


positive/elevated nitroprusside

Glucose False Interferes with the copper


positive/elevated reduction assay

Cefditoren pivoxil Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Cefepime Anti-bacterial Glucose False Interferes with the copper


hydrochloride agent positive/elevated reduction assay
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
Cefixime Anti-bacterial Ketone bodies and False Interferes with the copper
agent glucose positive/elevated reduction assay

Cefotaxime sodium Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Cefotetan disodium Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Creatinine* False Interferes with the Jaffé


positive/elevated reaction

Cefoxitin sodium Anti-bacterial Creatinine* False Interferes with the Jaffé


agent positive/elevated reaction
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17-hydroxycorticosteroids False Interferes with the


positive/elevated Porter-Silber reaction

Glucose False Interferes with the copper

D
positive/elevated reduction assay

Cefprozil Anti-bacterial Glucose* False Interferes with the copper

Ceftazidime
agent

Anti-bacterial
agent
Glucose FalseTE
positive/elevated

positive/elevated
reduction assay

Interferes with
reduction assay
the copper
EP
Ceftriaxone sodium Anti-bacterial Glucose False ND
agent positive/elevated

Ceftriaxone sodium Anti-bacterial Glucose False Interferes with the copper


C

agent positive/elevated reduction assay

Glucose* False Interferes with the ferricyanide


AC

negative/decreased assay

Cefuroxime sodium Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Glucose* False Interferes with the ferricyanide


ST

negative/decreased assay

Chlorpromazine Psychotropic drug Pregnancy tests* False ND


hydrochloride positive/elevated
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Cortisone acetate Anti-inflammatory Bacterial infection False Interferes with the


agent screening test* negative/decreased nitroblue-tetrazolium assay

Dactinomycin Anti-bacterial Antibacterial drug levels* ND ND


agent

Danazol Hormones, Testosterone, ND ND


hormone androstenedione and
substitutes, and dehydroepiandrosterone*
hormone
antagonists

Desvenlafaxine Psychotropic drug Phencyclidine and False Nonspecific antigen


Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
fumarate amphetamine positive/elevated interference
monohydrate

Desvenlafaxine Psychotropic drug Phencyclidine and False Nonspecific antigen


succinate amphetamine positive/elevated interference

Dexamethasone Hormones, Bacterial infection False Interferes with the


sodium phosphate hormone screening test* negative/decreased nitroblue-tetrazolium assay
substitutes, and
hormone
antagonists

Dextroamphetamine Central nervous Steroids ND ND


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sulfate system agent

Diatrizoate Contrast medium Proteinuria, specific ND ND


meglumine gravity, osmolality, and

D
bacterial cultures

Diatrizoate Contract medium Proteinuria, specific ND ND


meglumine

Diatrizoate sodium Contrast medium


gravity,

Proteinuria,
osmolality,
bacterial cultures
or

specific ND
TE Various
EP
gravity, osmolality, or
bacterial cultures

Doxycycline Anti-bacterial Catecholamines False Interferes with the


C

agent positive/elevated fluorescence assay

Doxycycline Anti-bacterial Catecholamines False Interferes with the


AC

hyclate agent positive/elevated fluorescence assay

Efavirenz Anti-infective Cannabinoid False Microgenics CEDIADAU


agent positive/elevated Multi-Level THC assay

Erythromycin Anti-bacterial Catecholamines ND Interferes with the fluorometric


ST

agent assay

Erythromycin Anti-bacterial Catecholamines ND Interferes with the fluorometric


ethylsuccinate agent assay

Erythromycin Anti-bacterial Catecholamines ND Interferes with the fluorometric


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lactobionate agent assay

Erythromycin Anti-bacterial Catecholamines ND Interferes with the fluorometric


stearate agent assay

Etodolac Analgesic Bilirubin, ketone bodies False Due to the presence of


positive/elevated phenolic metabolites of
etodolac

Ezogabine Central nervous Bilirubin* False ND


system agent positive/elevated

Fludrocortisone Anti-inflammatory Bacterial infection False Interferes with


Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
acetate agent screening test* negative/decreased nitroblue-tetrazolium assay

Gabapentin Analgesic Protein False Interferes with the Ames


positive/elevated n-Multistix sg dipstick assay

Iodixanol Contrast media Protein False Interferes with the Multistix


positive/elevated reagent

Labetalol Adrenergic agent Catecholamines, False Interferes with fluorimetric or


hydrochloride metanephrine, positive/elevated photometric assays
normetanephrine, and
vanillylmandelic acid

Amphetamine False Interferes with thin-layer


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positive/elevated chromatographic assays


®
(Toxi-Lab A ) and
radioenzymatic assays

D
®
(Emit-d.a.u .)

Levofloxacin Anti-bacterial Opiate False Interferes with immunoassay

Mefenamic acid
agent

Analgesic Bilirubin False


TE
positive/elevated

positive/elevated
Interferes with dinitrosalicylic
acid assay
EP
Mesna Antidote Ketones False Interferes with nitroprusside
positive/elevated sodium-based assay

Creatinine False Interferes with the thiol


C

phosphokinase* negative/decreased compound (e.g.,


n-acetylcysteine) for CPK
AC

reactivation

Ascorbic acid False Interferes with Tillman's


positive/elevated reagent-based assays

Metaxalone Peripheral nervous Glucose False Interferes with the copper


ST

system agent positive/elevated reduction assay

Methenamine Anti-infective Estriol False Interferes with assays


hippurate agents negative/decreased involving acid hydrolysis

Methocarbamol Central nervous 5-hydroxyindoleacetic ND Interferes with the assays using


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system agent acid nitrosonaphthol

Vanillylmandelic acid ND Interferes with assays using the


Gitlow method

Methyldopa Adrenergic agent Uric acid ND Phosphotungstate method


Catecholamines False Fluorescence in urine samples
positive/elevated at the same wavelengths as
catecholamines

Methyldopate Adrenergic agent Uric acid ND Phosphotungstate method


hydrochloride
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
Catecholamines False Fluorescence in urine samples
positive/elevated at the same wavelengths as
catecholamines

Metyrosine Antineoplastic Catecholamine ND ND


agent

Minocycline Anti-bacterial Catecholamine False Interferes with the


hydrochloride agent positive/elevated fluorescence test

Nafcillin sodium Anti-bacterial Protein False Interferes with the


agent positive/elevated sulfosalicyclic acid test

Nalbuphine Analgesic Opioids ND Interferes with enzymatic


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hydrochloride methods

Naproxen Analgesic 17-ketogenic steroids False Interaction between the drug


positive/elevated and/or its metabolites with the

D
m-di-nitrobenzene used in this
assay

Naproxen sodium Analgesic


5-hydroxy
acid (5hiaa)
indoleacetic

17-ketogenic steroids
ND

False
TE ND

Interaction between the drug


EP
positive/elevated and/or its metabolites with the
m-di-nitrobenzene used in this
assay
C

5-hydroxy indoleacetic ND ND
acid (5hiaa)
AC

Niacin Cardiovascular Catecholamines* False Interferes with fluorometric


agent positive/elevated determinations

Glucose False Interferes with the copper


positive/elevated reduction assay
ST

Nitrofurantoin Anti-infective Glucose False Interferes with the copper


agent positive/elevated reduction assay

Nizatidine Anti-ulcer agent Bilirubin False Interferes with the Multistix


positive/elevated reagent
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Ofloxacin Anti-bacterial Opiates False Interferes with enzymatic


agent positive/elevated methods

Oxaprozin Analgesic Benzodiazepines False Interferes with immunoassay


positive/elevated

Palivizumab Anti-infective Immunological-based rsv ND Interferes with


agent diagnostic tests, viral immunological-based rsv
culture assays* diagnostic tests

Pantoprazole Anti-ulcer agent Tetrahydrocannabinol False ND


sodium (thc) positive/elevated
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
Penicillin g Anti-bacterial Glucose False Interferes with copper
potassium agent positive/elevated reduction assay

Protein False ND
positive/elevated

Penicillin g sodium Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay

Protein False ND
positive/elevated

Piperacillin sodium Anti-bacterial Glucose False Interferes with the copper


agent positive/elevated reduction assay
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Aspergillus eia test* False Cross-reactions with the


positive/elevated Bio-Rad Laboratories Platelia®

Prazosin Adrenergic agent Vma and metabolite of False ND

D
hydrochloride norepinephrine positive/elevated

Prochlorperazine Psychotropic drug Pku, pregnancy tests* False ND


maleate

Promethazine
hydrochloride
Anti-allergic agent Pregnancy tests* TE
positive/elevated

False-negative or
false-positive
ND
EP
Pyrazinamide Anti-bacterial Ketone bodies False Interferes with the Acetest®
agent positive/elevated and Ketostix® test strips

Quetiapine Psychotropic drug Methadone and tricyclic False Interferes with enzyme
C

fumarate antidepressants positive/elevated immunoassays

Quinine sulfate Anti-infective Protein ND Interferes with the pyrogallol


AC

agent red-molybdate assay

17-ketogenic steroids False Interferes with the Zimmerman


positive/elevated method

Ranitidine Anti-ulcer agent Protein False Interferes with the Multistix®


ST

hydrochloride positive/elevated reagent

Rifampin Anti-bacterial Opiates False Interferes with the KIMS


agent positive/elevated (kinetic interaction of
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microparticles in solution)
method

Sertraline Psychotropic drug Benzodiazepines False Interferes with screening


hydrochloride positive/elevated immunoassay

Sotalol Adrenergic agent Metanephrine False Interferes with fluorometric or


hydrochloride positive/elevated photometric methods

Spironolactone Hormones, Digoxin* ND Interferes with


hormone radioimmunoassay
substitutes, and
hormone
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known)
test(s) or assay affected
antagonists

Succimer Antidote Ketones False Interferes with nitroprusside


positive/elevated reagents such as Ketostix®

Sulfasalazine Analgesic Normetanephrine False Interferes with liquid


positive/elevated chromatography method

Telavancin Anti-bacterial Protein ND Interferes with urine


hydrochloride agent qualitative dipstick protein
assays and quantitative dye
methods (e.g., pyrogallol
red-molybdate)
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Thioridazine Psychotropic drug Pregnancy tests* False ND


hydrochloride positive/elevated

Tolbutamide Hypoglycemic Albumin False The acidification-after-boiling

D
agent positive/elevated test

Tolmetin sodium Analgesic Protein False Interference of tolmetin

TE
positive/elevated sodium metabolite in urine in
tests that rely on
precipitation as their endpoint
acid
EP
(e.g., sulfosalicylic acid).

Triamterene Diuretic Quinidine* False Triamterene and quinidine


positive/elevated have similar fluorescence
C

spectra

Venlafaxine Psychotropic drug Phencyclidine and False Immunoassay screening tests


AC

hydrochloride amphetamine positive/elevated

Vigabatrin Cns agent Amino acids False ND


positive/elevated

* the assay may be performed on more than one type of matrix (e.g., serum or urine), or the matrix was
ST

not specified in the DailyMed label


ND, not documented/not described (this information was not included in the DailyMed label)
JU
Table 2. FDA-approved single-ingredient drugs that affect blood-based assays
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known) or
test(s) assay affected
Alteplase Cardiovascular Coagulation tests and unreliable Degradation of fibrinogen
agent fibrinolytic activity

Aminocaproic Hematological Template bleeding time false Inhibits ADP and collagen-induced
acid agent positive/elevated platelet aggregation, the release of
ATP and serotonin, and the binding
of fibrinogen to platelets

Aminosalicylic Anti-bacterial Albumin ND Dye-binding method


acid agent Ast ND Azoene dye method

Amphotericin b Anti-infective Phosphate false PHOSm assay


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agent positive/elevated

Anti-thymocyte Immunological Rabbit antibody-based ND Non-specific reaction


globulin (rabbit) factor immunoassays and

D
cross-match or
panel-reactive antibody

Capromab
pendetide
Indicator/reagent
cytotoxicity assays

Some antibody-based
immunoassays (incl.
false TE
positive/elevated
Presence of human anti-mouse
antibody
EP
PSA and digoxin)

Carbamazepine Analgesic Pregnancy tests* ND ND

Cefadroxil Anti-bacterial Direct Coombs' tests false ND


C

agent positive/elevated

Cefadroxil Anti-bacterial Direct Coombs' tests false ND


AC

hemihydrate agent positive/elevated

Cefazolin Anti-bacterial Direct Coombs' tests false ND


agent positive/elevated

Cefdinir Anti-bacterial Susceptibility results for false ND


ST

monohydrate agent Citrobacter, positive/elevated


Providencia, and
Enterobacter spp.*

Direct Coombs’ test false ND


JU

positive/elevated

Cefditoren Anti-bacterial Direct Coombs' tests false ND


pivoxil agent positive/elevated

Cefixime Anti-bacterial Direct Coombs' tests false ND


agent positive/elevated

Cefotetan Anti-bacterial Creatinine* false Interferes with the Jaffé reaction


disodium agent positive/elevated

Cefoxitin sodium Anti-bacterial Creatinine* false Interferes with the jaffé reaction
agent positive/elevated
Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known) or
test(s) assay affected
Cefpodoxime Anti-bacterial Direct Coombs' tests false ND
proxetil agent positive/elevated

Cefprozil Anti-bacterial Glucose* false Interferes with the copper


agent positive/elevated reduction assay

Glucose false negative Interferes with the ferricyanide


assay

Ceftibuten Anti-bacterial Direct Coombs' tests false ND


dihydrate agent positive/elevated

Ceftriaxone Anti-bacterial Glucose* false Interferes with the ferricyanide


sodium agent negative/decreased assay
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Cefuroxime Anti-bacterial Glucose* false Interferes with the ferricyanide


sodium agent negative/decreased assay

Cephalexin Anti-bacterial Direct Coombs' tests false ND

D
agent positive/elevated

Certolizumab Immunological Activated partial false Interferes with certain coagulation


pegol

Chlorpromazine
factor

Psychotropic drug
thromboplastin
(aptt) assay

Phenylketonuria (PKU)
time

false
TE
positive/elevated assays

ND
EP
hydrochloride test positive/elevated

Pregnancy tests* false ND


positive/elevated
C

Cortisone acetate Anti-inflammatory Bacterial infection false Interferes with the


agent screeing test* negative/decreased nitroblue-tetrazolium assay
AC

Dactinomycin Anti-bacterial Antibacterial drug ND ND


agent levels*

Danazol Hormones, Testosterone, ND ND


hormone androstenedione and
ST

substitutes, and dehydroepiandrosterone*


hormone
antagonists
JU

Daptomycin Anti-bacterial PT and INR False Interacts with recombinant


agent positive/elevated thromboplastin

Dexamethasone Hormones, Bacterial infection False Interferes with the


sodium hormone screeing test* negative/decreased nitroblue-tetrazolium assay
phosphate substitutes, and
hormone
antagonists

Dextran 40 Anticoagulant Glucose False ND


positive/elevated

Bilirubin, protein False Development of turbidity


Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known) or
test(s) assay affected
positive/elevated

Diatrizoate Contrast medium Fibrinogen False Development of turbidity


meglumine concentration; factors V, negative/decreased interfering with the assay
VII, and VIII; platelet
aggregation; serum
calcium; red cell counts;
leukocyte counts

Prothrombin and False ND


thromboplastin times, positive/elevated
urea nitrogen (BUN),
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serum creatinine, red


blood cell counts,
leukocyte counts

D
Diatrizoate Contrast medium Fibrinogen False Development of turbidity
sodium concentration; factors V, negative/decreased interfering with the assay
VII, and VIII; platelet
aggregation; serum
calcium; red cell counts;
TE
EP
leukocyte counts

Prothrombin and False Various


thromboplastin times, positive/elevated
urea nitrogen (BUN),
C

serum creatinine, red


AC

blood cell counts,


leukocyte counts

Diflunisal Analgesic Salicylate False ND


positive/elevated

Edetate disodium Anticoagulant Calcium False Interferes with the oxalate method
ST

negative/decreased

Ezogabine Central nervous Bilirubin* False ND


system agent positive/elevated
JU

Fenoprofen Anti-inflammatory Total and free False Chemical cross-reaction


calcium agent triiodothyronine positive/elevated

Fludrocortisone Anti-inflammatory Bacterial infection False Interferes with


acetate agent screeing test* negative/decreased nitroblue-tetrazolium assay

Fosinopril Cardiovascular Digoxin False Interferes with the


sodium agent negative/decreased Digi-Tab®“ RIA Kit

Gadodiamide Contrast media Calcium False Interferes with the colorimetric


negative/decreased assay

Gadoversetamide Contrast media Iron, copper, zinc ND ND


Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known) or
test(s) assay affected
Calcium False decreased Interferes with the
ortho-cresophthalin complexone
(ocp) colorimetric assay

Gadoxetate Contrast media Iron False Due to the presence of caloxetate


disodium negative/decreased trisodium excipients when using
complexometric methods
(ferrocene complexation method)

Iopromide Contrast media Coagulation and False ND


fibrinolysis assay positive/elevated

Iron dextran Hematological Bilirubin False ND


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agent positive/elevated

Calcium False Gives a brown color to serum


negative/decreased

D
Isoproterenol Adrenergic agent Bilirubin False ND
sulfate positive/elevated

Isosorbide
mononitrate

Isosulfan blue
Cardiovascular
agent

Coloring agent
Cholesterol

Oxygen saturation
False

TE
negative/decreased

False
Interferes with the Zlatkis-Zak
color reaction

Pulse oximetry
EP
negative/decreased

Methemoglobin False Arterial blood gas analyzers


positive/elevated
C

Kanamycin Anti-bacterial Creatinine False ND


sulfate agent positive/elevated
AC

Mesna Antidote Creatinine False Interferes with the thiol compound


phosphokinase* negative/decreased (e.g., N-acetylcysteine) for CPK
reactivation

Methyldopa Adrenergic agent Creatinine ND Alkaline picrate method


ST

SGOT ND Colorimetric methods

Methyldopate Adrenergic agent Creatinine ND Alkaline picrate method


hydrochloride
SGOT ND Colorimetric methods
JU

Metronidazole Anti-infective SGOP, SGPT, LDH, ND Similarity in the absorbance peaks


agent triglycerides, hexokinase of NADH (340 nm) and
glucose metronidazole (322 nm) at pH 7.

Niacin Cardiovascular Catecholamines* False Interferes with fluorometric


agent positive/elevated determinations

Nitroglycerin Cardiovascular Cholesterol False Interferes with the Zlatkis-Zak


agent negative/decreased color reaction

Ovine digoxin Immunologic Digoxin ND Nonspecific antigen interference


immune fab factor

Palivizumab Anti-infective immunological-based ND Interferes with


Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known) or
test(s) assay affected
agent RSV diagnostic tests, immunological-based RSV
viral culture assays* diagnostic tests

Piperacillin Anti-bacterial Aspergillus EIA test* False Cross-reactions with the Bio-Rad
sodium agent positive/elevated Laboratories Platelia®

Prochlorperazine Psychotropic drug PKU, pregnancy tests* False ND


edisylate positive/elevated

Prochlorperazine Psychotropic drug PKU, pregnancy tests* False ND


maleate positive/elevated

Promethazine Anti-allergic agent Pregnancy tests* False-negative or ND


hydrochloride false-positive
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Rifampin Anti-bacterial Folate and vitamin B False Interferes with standard


negative/decreased microbiological assays for folate
and vitamin B

D
Rifapentine Anti-bacterial Folate and vitamin B False Interferes with standard
agent negative/decreased microbiological assays for folate

Spironolactone Hormones,
hormone
Digoxin* ND TE and vitamin B

Interferes with radioimmunoassay


EP
substitutes, and
hormone
antagonists
C

Succimer Antidote Uric acid and CPK False ND


negative/decreased
AC

Telavancin Anti-bacterial PT, INR, aPTT, and ACT False Telavancin binds to the artificial
hydrochloride agent positive/elevated phospholipid surfaces added to
common anticoagulation tests,
thereby
ST

interfering with the ability of the


coagulation complexes to assemble
on the surface of the
phospholipids and promoting
JU

clotting in vitro

Thioridazine Psychotropic drug pregnancy tests* False ND


hydrochloride positive/elevated

Tinidazole Anti-infective AST, ALT, LDH, ND Potential interference due to the


agent triglycerides, hexokinase similarity of absorbance peaks of
glucose NADH and tinidazole

Triamterene Diuretic Quinidine* False Triamterene and quinidine have


positive/elevated similar fluorescence spectra

Trifluoperazine Psychotropic drug Phenylketonuria (PKU) False ND


Drug Class or type Type of test(s) or Specific Mechanism of
of drug analyte(s) affected impact on interference (if known) or
test(s) assay affected
hydrochloride test positive/elevated

Trimethoprim Anti-bacterial Methotrexate ND Competitive binding protein


hydrochloride agent technique (CBPA) when a bacterial
dihydrofolate reductase is used as
the binding protein

Creatinine False Interferes with the Jaffé alkaline


positive/elevated picrate reaction assay

Vigabatrin Cns agent ALT, AST False ND


negative/decreased

*the assay may be performed on more than one type of matrix (e.g., serum or urine), or the matrix was
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not specified in the DailyMed label


ND, not described/not documented (this information was not included in the DailyMed label)

D
TE
EP
C
AC
ST
JU