Professional Documents
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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
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
Hui Yao1*, Elizabeth R. Rayburn2*, Qiang Shi3, Liang Gao1, Wenjie Hu1, Haibo Li1
1
Department of Clinical Laboratory Medicine, Nantong Maternity and Child Health
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
ntlihaibo2015@163.com
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labels, DailyMed
dedicated to improving the clinical laboratory sciences and promotes their application
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for healthcare
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ALT, alanine transaminase
Abstract
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.
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
warranted.
Introduction
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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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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
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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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
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
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
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
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
There are numerous requirements for method development that are considered by
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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
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
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
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
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
interference as they arise, because not all can be identified or examined during the
Drugs can impact the results of laboratory tests in several ways. One is by
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
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
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
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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[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
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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“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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“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
“Nitrates and nitrites may interfere with the Zlatkis-Zak color reaction, causing
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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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anti-infective agents were defined as all agents targeting microbes other than bacteria
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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indicated for problems with the circulatory system (e.g. anti-hypertensive drugs,
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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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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The most prominent finding of this study was that only 12.35% (169/1,368) of the
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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.
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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assays. In addition, almost all of the labels for these drugs recommend that glucose
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
incorrect diagnosis.
Some anti-bacterial agents can also interfere with the detection of the clotting
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
Psychotropic drugs The psychotropic drugs were found to be the second most likely
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drugs are similar to those of the other psychotropic drugs or their metabolites. This
clinicians (or by the agency performing employee drug testing), because it may lead
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
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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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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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(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
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
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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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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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collection. In addition, urine is particularly important for the screening of illegal drugs
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
etc.), while blood is more often used for immediate decision-making regarding
hemoglobin level, blood gases, liver enzyme levels, etc.). Thus, while it may be less
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
detection by the copper reduction assay. As noted in the section above, several other
shown in Tables 1 and 2, cefdinir interferes with glucose detection via specific assays;
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.
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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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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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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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
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
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
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
the HbA1c, may indicate that part of the testing was affected and raise a flag that there
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
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
determined by the Jaffé reaction, since Ancobon does not interfere with the
measurement of creatinine makes use of the Jaffé reaction.” The information for
gadopentetate dimeglumine injection notes that “MAGNEVIST Injection does not
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
in the drugs labels. Although this is helpful and represents a good start to
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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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
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
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
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.
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
testing, or testing of a new sample) may lead to correction of a spurious result without
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
Warning Sections of Labeling for Human Prescription Drug and Biological Products
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
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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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.
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
ideal “first-line” for detecting potential DLTI. They have extensive knowledge about
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the reagents being used, including proprietary information that may not be available
to others but that might help to predict interactions. The current FDA
guidelines
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(http://www.iso.org/iso/home/store/catalogue_tc/catalogue_tc_browse.htm?commid=
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.
DLTI during clinical trials. Clinical trials have strict inclusion and exclusion criteria
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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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
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
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
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
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,
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
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
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
compared to those obtained before the drug was taken) will be particularly helpful in
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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
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
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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than those managing the database. This allowa the accuracy of the data regarding
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
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
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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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
ability to crowd-source data regarding suspected DLTI would also likely accelerate
research on the topic.
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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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.
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
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
serve as a reference for physicians and clinical laboratory staff to obtain better test
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Acknowledgement
Dr. Haibo Li was supported in part by the International Cooperation and Exchanges
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
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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
positive/elevated
methods
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positive/elevated reduction assay
Ceftazidime
agent
Anti-bacterial
agent
Glucose FalseTE
positive/elevated
positive/elevated
reduction assay
Interferes with
reduction assay
the copper
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Ceftriaxone sodium Anti-bacterial Glucose False ND
agent positive/elevated
negative/decreased assay
negative/decreased assay
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bacterial cultures
Proteinuria,
osmolality,
bacterial cultures
or
specific ND
TE Various
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gravity, osmolality, or
bacterial cultures
agent assay
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®
(Emit-d.a.u .)
Mefenamic acid
agent
positive/elevated
Interferes with dinitrosalicylic
acid assay
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Mesna Antidote Ketones False Interferes with nitroprusside
positive/elevated sodium-based assay
reactivation
hydrochloride methods
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m-di-nitrobenzene used in this
assay
17-ketogenic steroids
ND
False
TE ND
5-hydroxy indoleacetic ND ND
acid (5hiaa)
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Protein False ND
positive/elevated
Protein False ND
positive/elevated
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hydrochloride norepinephrine positive/elevated
Promethazine
hydrochloride
Anti-allergic agent Pregnancy tests* TE
positive/elevated
False-negative or
false-positive
ND
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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
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microparticles in solution)
method
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agent positive/elevated test
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positive/elevated sodium metabolite in urine in
tests that rely on
precipitation as their endpoint
acid
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(e.g., sulfosalicylic acid).
spectra
* 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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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
agent positive/elevated
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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
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PSA and digoxin)
agent positive/elevated
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
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agent positive/elevated
Chlorpromazine
factor
Psychotropic drug
thromboplastin
(aptt) assay
Phenylketonuria (PKU)
time
false
TE
positive/elevated assays
ND
EP
hydrochloride test positive/elevated
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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
Edetate disodium Anticoagulant Calcium False Interferes with the oxalate method
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negative/decreased
agent positive/elevated
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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
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negative/decreased
Piperacillin Anti-bacterial Aspergillus EIA test* False Cross-reactions with the Bio-Rad
sodium agent positive/elevated Laboratories Platelia®
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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
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
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clotting in vitro
*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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