Jurnal Sabila

Drug Interactions: Scientific and
Clinical Principles
By Michael Gabay, Pharm.D., JD, FCCP, BCPS; and Samantha H. Spencer, Pharm.D., BCPS
Reviewed by Robert D. Beckett, Pharm.D., BCPS; and Janine S. Douglas, Pharm.D., BCPS
LEARNING OBJECTIVES
1. Assess patients on the basis of the incidence of drug interactions and their potential outcomes.
2. Distinguish the mechanisms behind various drug interactions and their impact on patients.
3. Develop strategies for identifying and mitigating potential drug interactions.
4. Evaluate the strengths and weaknesses of available drug interaction resources.
INTRODUCTION
ABBREVIATIONS IN THIS CHAPTER
Drug interactions occur when the concomitant administration of
CDS Clinical decision support
another drug or substance affects a drug’s effect. The results of
CMM Comprehensive medication
management these interactions range on a scale of clinical importance, with some
DART Drug-Associated Risk Tool resulting in serious harm, some having no significant clinical impact,
DDI Drug-drug interaction and some resulting in beneficial, synergistic effects. Although clin-
OATP Organic anion-transporting ical pharmacists are familiar with the common underlying mecha-
polypeptide nisms of drug interactions, additional pharmacokinetic mechanisms
have been elucidated in recent years, and interest has increased in
Table of other common abbreviations. the role of pharmacogenetics on the clinical significance of interac-
tions. For example, the FDA first addressed interactions involving
organic anion-transporting polypeptide (OATP) in its 2012 drug-drug
interaction (DDI) guidance for industry, and since then, the number
of known OATP substrates and inhibitors identified has increased
(McFeely 2019). Genetic polymorphisms have also increasingly been
studied to elucidate their impact on DDIs and drug-drug-gene inter-
actions (Bahar 2017).
In addition to growing research and understanding in this area,
increasing polypharmacy leads to an increased potential for interac-
tions. According to the National Center for Health Statistics, 22.4% of
American adults 40–79 years of age used five or more prescription
medications in the prior month in 2015–2016 (Hales 2019). In addi-
tion, an analysis of the prevalence of medication use and subsequent
risk of DDIs among older adults found that concurrent use of five or
more prescription medications increased from 30.6% in 2005–2006
to 35.8% in 2010–2011, and use of dietary supplements increased
from 51.8% to 63.7% during the same time (Qato 2016). Further anal-
ysis found that 15.1% of older adults in the 2010–2011 cohort were
using drug combinations that could result in a major DDI, compared
with 8.4% in 2005–2006. Thus, clinical pharmacists should be cogni-
zant of recent research into new mechanisms, strategies for manag-
ing drug interactions, and available resources for identifying them.
PSAP 2021 Book 3 • Chronic Conditions and Public Health 7 Drug Interactions: Scientific and Clinical Principles
Prevalence of DDIs range of reported prevalence values, ranging from 1.2% in
The true prevalence of drug interactions is difficult to define one cohort of internal medicine patients to 64% in a cohort
and quantify. First, prevalence depends on the types of drug of patients in the ICU (Gonzaga de Andrade Santos 2020).
interactions included in an analysis because many drug inter- The pooled prevalence of clinically manifested DDIs was 9.2%
actions are not clinically significant or are based only on (95% CI, 4.0–19.7). In another systematic review, the preva-
theoretical data. Potential DDIs should be considered sepa- lence of potential DDIs in the inpatient setting was analyzed
rately from clinically relevant DDIs because not all patients (Zheng 2018). Potential DDIs were defined as those detected
will experience an adverse event, even when taking a com- on the basis of information in drug compendia regardless of
bination of drugs known to interact. Recent researchers in clinical manifestations. Twenty-seven studies were included
this area have tried to account for this issue by selecting only in the analysis, with 17 studies that were conducted in devel-
clinically relevant interactions, defined as those that lead oping countries (e.g., India, Pakistan) and 18 studies that
to a clinical consequence such as adverse events. Despite included general inpatients, excluding ICU patients. The
these limitations, the prevalence of DDIs has been evaluated pooled prevalence of patients with at least one potential DDI
in several studies, particularly in the hospital setting, where in the non-ICU population was 33% (95% CI, 17.3–51.3). In the
patients may be exposed to more drugs and/or more complex ICU population, the pooled prevalence was 67% (95% CI, 52.7–
regimens during their inpatient stay. 79.1). The pooled data showed high heterogeneity (I2 greater
A systematic review of 10 observational studies that eval- than 97%) across both populations.
uated confirmed, clinically manifested DDIs found a wide
Potential Outcomes of Drug Interactions
Because not all DDIs have clinically significant conse-
quences, the epidemiologic impact of DDIs should be
BASELINE KNOWLEDGE STATEMENTS assessed through realized DDIs and their clinical outcomes.
Clinical outcomes from DDIs have mainly been studied within
Readers of this chapter are presumed to be familiar
with the following: the realm of hospital-related outcomes, including adverse
drug events and risk of hospitalization or increased length
• General knowledge of the types of drug interac-
of stay. Thus, the focus of most research has been on DDIs
tions (e.g., drug-drug, drug-food)
that result in adverse events, excluding therapeutic failures
• The difference between pharmacokinetic and
pharmacodynamic drug interactions or synergistic interactions.
The proportion of hospital admissions that could be
• Comprehensive medication management as a
standard-of-care approach to ensuring each attributed to DDIs was evaluated in a systematic review of
medication is safe, given patient comorbidities 13 studies (Dechanont 2014). From a pooled population of
and concurrent medications 47,976 hospital admissions, 1.1% (interquartile range [IQR]
• The basic availability of drug interaction tertiary 0.4%–2.4%) were associated with DDIs. Looking more specif-
resources ically at the 1683 hospitalizations associated with adverse
drug reactions, 22.2% (IQR 16.6%–36.0%) were attributed to
Table of common laboratory reference values
DDIs. In addition, five of the studies included in the review
reported the interacting drugs; the most commonly reported
ADDITIONAL READINGS DDIs were aspirin-NSAID or NSAID-NSAID interactions lead-
ing to GI bleeding, together with interactions of digoxin with
The following free resources have additional back-
ground information on this topic: other cardiovascular drugs (e.g., verapamil) leading to cardio-
vascular rhythm disturbances.
• U.S. Food and Drug Administration (FDA). Tables
Drug-drug interactions are also associated with increased
for Substrates, Inducers, and Inhibitors.
hospital length of stay. Data fully describing these outcomes
• U.S. Food and Drug Administration (FDA). Drug
Interactions: What You Should Know. are not very robust. However, one retrospective single-center
evaluation found that the average length of stay in a cohort of
• U.S. Food and Drug Administration (FDA). CDER
Conversation: Evaluating the Risk of Drug-Drug patients with a potential severe or moderate DDI during hospi-
Interactions. talization was 15 days compared with 8 days in patients who
• U.S. Food and Drug Administration (FDA). Prevent- did not have a potential DDI identified during the same period
able Adverse Drug Reactions: A Focus on Drug (Moura 2009).
Interactions. Drug-drug interactions can also result in a reduction or
• Carpenter M, Berry H, Pelletier AL. Clinically loss of efficacy for one of the involved drugs, which typically
relevant drug-drug interactions in primary care. occurs when the metabolism of one drug is induced or if there
Am Fam Physician 2019;99:558-64.
are antagonizing effects of the two interacting drugs. Result-
ing therapeutic failure from actual DDIs has not been as well
characterized; some studies have reported that the percent- the most commonly documented DDI mechanisms. A discus-
age of adverse DDIs leading to failure of efficacy ranges from sion of several of these mechanisms follows to help charac-
8.6% to 11.6% (Magro 2012). terize the varying incidence and relevance of DDIs.
Enzyme inhibition and induction mechanisms are well doc-
MECHANISMS OF DRUG umented, with phase I oxidation by CYP isoenzymes being the
INTERACTIONS most characterized and well understood. These interactions
Many DDIs occur through common mechanisms related to the can further be classified by their degree of inhibition or induc-
pharmacokinetics and pharmacodynamics of the interacting tion (e.g., potent, moderate, weak). Enzyme inhibition is more
drugs. Although there are unique or unusual mechanisms for common than enzyme induction. Inhibition also has faster
interactions for certain combinations, Table 1 summarizes onset than induction, which requires time to synthesize more
Table 1. Overview of Common DDI Mechanisms
Category Type of Interaction Overview Example
Absorption Changes in GI pH Alterations in pH by one drug Decreased bioavailability of posaconazole oral

resulting in altered absorption suspension with administration of PPIs
of another drug
Adsorption, Drug binding another drug to Administration of antacids with tetracyclines

chelation, or reduce absorption leading to poorly soluble chelates, reducing
complexing tetracycline absorption
Changes in GI Changes in transit time Increased cyclosporine exposure when given

motility affecting absorption with metoclopramide because of enhanced gut
motility by metoclopramide
Modulation of Changes in absorption of a Induction of P-glycoprotein with rifampin leads

drug transporter drug from the GI tract because to decreased absorption of digoxin because of
proteins of inhibition or induction of decreased GI absorption and increased biliary
drug transporter proteins excretion
Distribution Protein binding Competition for binding Increased risk of supratherapeutic

sites on serum proteins concentrations of warfarin with
between drugs, resulting in coadministration of valproic acid because
displacement of displacement of warfarin from protein
binding sites (and CYP2C9-mediated warfarin
metabolism inhibition)
Modulation of Changes in uptake of a drug Increased exposure of ritonavir in the CNS

drug transporter to a site of action because of through ketoconazole induced–inhibition of
proteins inhibition or induction of drug P-glycoprotein leading to reduced transport out
transporter proteins of the CNS
Metabolism Changes in first- Alteration of portal circulation Increased dofetilide concentrations and risk of QT
pass metabolism flow by one drug affects prolongation with administration of verapamil,
the extent of first-pass which is thought to increase absorption through
metabolism of another drug increased hepatic blood flow
Enzyme induction Increase in synthesis of an Decreased simvastatin concentrations when

isoenzyme responsible for administered with carbamazepine, an inducer
metabolism of a drug of CYP3A4, which is the primary metabolizing
enzyme for simvastatin
Enzyme inhibition Inhibition of an isoenzyme Increased warfarin concentrations when

responsible for metabolism of administered with amiodarone, an inhibitor
a drug of CYP2C9, CYP3A4, and CYP1A2, which all
contribute to the metabolism of warfarin
(continued)
Table 1. Overview of Common DDI Mechanisms (continued)
Category Type of Interaction Overview Example
Excretion Changes in urinary Alteration of urine pH by Analgesic dose aspirin serum concentrations
pH one drug leads to increased decrease with administration of antacids, which
excretion or retention of increases both urine pH and renal excretion
another drug
Changes in active Competition for active Salicylates (e.g., aspirin) competitively inhibit
renal tubular transport systems in renal the renal tubular elimination of methotrexate,
excretion tubules or alteration of drug leading to increased methotrexate exposure
transporter proteins in the
kidney that affects elimination
Enterohepatic Enterohepatic recirculation is Cholestyramine reduces the enterohepatic

shunt affected by one drug leading recirculation of mycophenolate by binding free
to reduced recirculation of mycophenolic acid in the GI tract
another drug, affecting its
overall exposure
Pharmacodynamic Additive or Drugs with the same Concomitant administration of opioids and
synergistic pharmacologic effect are benzodiazepines, leading to an increased risk of
interactions given together, resulting in drowsiness, respiratory depression
additive effects
Antagonistic Drugs with opposite Blood glucose–lowering effects of antidiabetics

or opposing pharmacologic effects are are opposed by corticosteroid-induced
interactions given together, resulting in hyperglycemia
opposing effects
Uptake Drug or Drugs occupy receptors on Response to norepinephrine is greatly increased

neurotransmitter adrenergic neurons, leading when given with TCAs, which inhibit reuptake of
uptake to altered uptake, reuptake, or norepinephrine at adrenergic neurons, leading
receptor interactions of drugs to hypertension
that are active at adrenergic
neurons
DDI = drug-drug interaction; PPI = proton pump inhibitor; TCA = tricyclic antidepressant.
Information from: Preston CL. Stockley’s Drug Interactions, 12th ed. London: Pharmaceutical Press, 2019.
isoenzymes. The clinical impact of enzyme inhibition and Other mechanisms, such as protein binding interac-
induction depends on the therapeutic index of the affected tions, often do not result in clinically relevant interactions
substrate. For example, a drug with a wide therapeutic index unless mediated by other factors. These interactions gen-
that interacts with an enzyme inhibitor/inducer may not erally only affect drugs where most of the drug remains in
result in a clinically meaningful interaction, even if the serum the plasma, or those with a low apparent volume of distri-
concentrations of the drugs are decidedly altered. These bution (Preston 2019). The impact of drug displacement of
interactions can also occur with prodrugs that require CYP highly protein bound drugs can be muted through a compen-
metabolism to its active metabolite; these lead to an opposite satory increase in metabolism and clearance of the newly
result from the classic inhibition, leading to increased concen- released, unbound active drug. Specifically, the interaction
trations, with inhibition of an activating CYP enzyme leading is unlikely to be clinically important if the affected drug has
to decreased active drug concentrations. Another challenge a low extraction ratio (i.e., minority of the drug is eliminated
becoming more prominent with polypharmacy is the poten- through a single mechanism of the eliminating organ). Many
tial for multidrug interactions, in which several coadminis- drugs that are highly protein bound also have low extraction
tered drugs are substrates/inducers/inhibitors of the same ratios (e.g., warfarin, phenytoin), so the resulting drug expo-
CYP enzyme, or more than one CYP metabolism pathway for sure from DDIs is not highly affected by changes in protein
a drug is affected by the presence of several inhibitors (Roug- binding. In addition, the clinical impact of protein binding
head 2015). interactions is tied to the distribution of the drug, where
drugs with a lower apparent volume of distribution are more major cardiac adverse effects of cisapride were identified in
likely to be affected. the postmarketing setting through adverse event reporting,
Drug transporter proteins represent another mecha- where most reports occurred in patients taking interacting
nism for DDIs that can affect drug absorption, distribution, medications or having underlying conditions that increased
or elimination. These proteins can be classified into two the risk of ventricular arrhythmias, which led to discontinu-
groups: the ATP-binding cassette family and the solute car- ation of the drug in the United States (Wysowski 2001). This
rier superfamily; the best-known examples of these groups example highlights the importance of continuous surveillance
are P-glycoprotein and OATP, respectively (Preston 2019). and the need for health care professionals to report adverse
Drug transporter proteins affect the pharmacokinetics of events in the postmarketing space. Potential clinically rele-
drugs within the body through uptake and efflux actions vant DDIs can also be identified through case reports/series
(König 2013). The resulting action of P-glycoprotein inhibi- and other retrospective evaluations. Retrospective cohort
tion depends on the site of the interaction. For instance, inhi- studies can particularly help identify clinically relevant DDIs,
bition of P-glycoprotein in enterocytes leads to increased given their ability to evaluate a large number of patients, typi-
oral bioavailability, whereas inhibition of P-glycoprotein in cally through insurance claims data, where potential DDIs can
the liver or kidney can result in reduced drug elimination. further be analyzed to measure associations with resulting
Hepatic uptake can be affected through OATP1B1 because adverse events (Chang 2017).
it affects that amount of drug entering hepatocytes, the site However, the strength of evidence supporting a DDI can be
of major metabolism pathways. The best-characterized DDIs poor. Of interest, in an analysis of 58 major or contraindicated
related to OATP1B1 involve statins. Inhibition of OATP1B1, for DDIs for psychotropic drugs, only one-third of the interactions
instance, can lead to increased serum plasma concentrations had supporting evidence from controlled studies showing an
of statins, increasing the risk of adverse effects. impact on drug plasma concentrations (Nguyen 2020). Even
Overall, however, these various mechanisms do not occur more limited data were available for controlled studies show-
in a vacuum, and a particular DDI may be the result of more ing a clinical impact on the resulting DDI. Furthermore, only 7
than one mechanism. Further complicating the understand- of the 58 evaluated DDIs had underlying evidence from stud-
ing of DDIs is the overlap of drugs that affect both drug trans- ies with at least 100 patients. This analysis highlights the
porter proteins and the CYP system. In particular, many drugs need for clinical pharmacists to evaluate the supporting data
are a substrate/inhibitor/inducer of P-glycoprotein together for a potential DDI and understand the relative strengths and
with CYP3A4 (Preston 2019). weaknesses of the available data.
Establishing Evidence for Drug Interactions Drug-Drug-Gene Interactions

Inhibition and induction of specific CYP isoenzymes and drug The CYP isoenzymes and P-glycoprotein are associated with
transporter proteins are evaluated primarily through in vitro genetic polymorphisms that can affect their functional capac-
studies using specific probe substrates (FDA 2020b). Inhibi- ity. Genetic polymorphisms within the CYP system are well
tion and induction are assessed during clinical development characterized, with CYP2C9, CYP2C19, and CYP2D6 being the
after characterizing the route of elimination and the impact best-understood isoenzymes. The metabolizing capacity of
of enzymes and transporters on the drug, together with the isoenzymes is categorized into different phenotypes, namely
drug’s effect on enzymes and transporters. This informa- extensive or poor metabolizer or expressers or non-expressers.
tion combined with pharmacokinetic data informs the in vitro The presence of genetic polymorphisms leads to some
studies that should be conducted. Subsequently, the clinical notable circumstances related to DDIs. First, in studying
impact of the interaction can further be assessed through and identifying potential DDIs, data showing the difference
clinical pharmacokinetic studies (FDA 2020a). Clinical DDI in drug exposure among patients who have different pheno-
studies use drugs known to be reliable inducers, inhibitors, types of an isoenzyme can help predict the potential for DDIs
or substrates of the enzyme or drug transporter protein. The with drugs that inhibit these isoenzymes. For instance, if
FDA provides a list of preferred substrates for these stud- there is no significant difference in the serum concentrations
ies on its website and in the clinical guidance for industry; of a drug in patients who are extensive versus poor metabo-
this guidance is currently limited to enzyme- and transport- lizers for a given isoenzyme, it is unlikely that a strong inhib-
mediated interactions. Familiarity with the content of this list itor of that isoenzyme will result in a clinically relevant DDI.
is imperative because it helps inform clinical pharmacists on Second, in evaluating a specific patient for potential DDIs,
the types of drug interactions likely to be known at the time knowledge of the patient’s polymorphisms can help identify
of a drug’s approval. whether a DDI is likely to be clinically relevant. For example, a
Some DDIs are not identified until the drug has been patient who is a poor metabolizer of a CYP isoenzyme would
approved, and there are notable examples of drugs that were be expected to be minimally affected by drugs that inhibit
removed from the market because of DDIs leading to seri- the CYP isoenzyme, so a clinically relevant DDI would not be
ous, potentially life-threatening adverse effects. For example, expected.
Characterizations of drug-drug-gene interactions have PREVENTION OF DRUG
identified three main categories of interactions: inhibitory, INTERACTIONS
induction, and phenoconversion (Malki 2020). Inhibitory and
induction interactions occur when both a perpetrator drug and Appropriate Prescribing and Risk Assessment
a genetic variant affect the pharmacokinetics of a victim drug. Clinical pharmacists should aim to prevent the potentially
The inhibitory or induction effect can either affect the same harmful effects of a drug interaction before it occurs. How-
isoenzyme or act in concert in two different routes of metabo- ever, because clinical pharmacists are unlikely to recollect
lism. For example, major metabolic pathways for voriconazole every potential drug interaction, use of a stepwise approach
include CYP2C9 and CYP2C19, with some minor involvement is key to preventing adverse reactions (FDA 2018). Essential
from CYP3A4 (Preston 2019). Coadministration with ritona- elements of this stepwise approach include incorporating
vir, a potent CYP2C19 inducer and CYP3A4 inhibitor, generally judicious prescribing concepts into patient care, identifying
decreases voriconazole exposure because of CYP2C19 induc- patients at high risk, obtaining a comprehensive medication
tion. However, in patients who are CYP2C19 poor metaboliz- (CMM) history, and consulting relevant general and special-
ers, voriconazole exposure may be increased as the inhibition ized resources as necessary.
of CYP3A4 from ritonavir dominates because these patients Although clinical pharmacists do not in many situations
have little to no CYP2C19 activity. Phenoconversion interac- have prescriptive authority, application of judicious prescrib-
tions occur when the perpetrator drug and genetic variant ing concepts can help clinical pharmacists develop a method
oppose each other, resulting in change of phenotype tempo- that emphasizes harmful interaction prevention, translating
rarily. For instance, a patient who is an ultra-rapid CYP2C19 to recommendations to prescribers with deterrence at the
metabolizer can have a drug exposure similar to a poor metab- forefront. Appropriate application of selected judicious pre-
olizer if given a CYP2C19 inhibitor (Malki 2020). Although scribing principles may prevent negative drug interactions
drug-drug-gene interactions are less well understood for drug using nondrug alternatives, encourage a focus on underlying
transporter proteins, some of these proteins are also subject causes of health concerns versus treatment of symptoms,
to genetic polymorphisms; these interactions can also be help with mastery of a more limited personal formulary for
grouped into the same three main categories. The Pharma- prescribing, assist with patient education regarding potential
cogenomics Knowledge Base is an accessible resource that adverse effects, enable greater collaboration with patients
characterizes some drug-drug-gene interactions. to optimize medication use, promote reassurance and close
patient follow-up, and encourage consideration of the long-
Drug–Natural Product Interactions term risk-benefit of drug therapy over the short-term impact.
Drug–natural product interactions are also important to note Clinical pharmacists may also need to reflect on a patient’s
and evaluate because the percentage of adults who use both or caregiver’s goals of therapy, the patient’s estimated life
prescription medications and natural products has increased; expectancy, cognitive impairment and visual dexterity con-
a 2015 survey of over 26,000 U.S. adults found that 35% of cerns, and adherence issues when considering the potential
respondents used at least one herbal supplement (Rashrash impact of drug interactions and recommendations to pre-
2017). In addition, the survey showed that respondents with scribers (Halli-Tierney 2019). Judicious prescribing, often
chronic diseases were more likely to use herbal supplements called conservative or cautious prescribing, consists of six
(e.g., prevalence of 43%, 41%, and 43% in patients with arthri- key principles that promote the effective and safe use of med-
tis, diabetes, and heart disease, respectively). Pharmacokinetic ications (Box 1) (Schiff 2011).
enzyme- and transport-mediated interactions are the most Clinical pharmacists should also assess patients for their
common mechanisms, or at least the most frequently docu- potential drug interaction risk. In general, any patient with a
mented, for drug–natural product interactions (Rombola 2020). medication regimen containing more than one drug or nat-
However, the data available on natural products are more ural product is at risk of developing a drug interaction (FDA
limited, with fewer in vitro studies and even fewer studies 2017). However, older adult patients who are more likely to
establishing clinically relevant DDIs. Further complicating the receive several medications for chronic conditions and those
interpretation of DDI data with natural products is the greater who may be prescribed many medications as part of standard
variation between different products of the same herb, and it treatment regimens for certain disease states (e.g., heart fail-
is sometimes not known which component of a supplement ure, diabetes) are at higher risk. One way to potentially iden-
is contributing to the drug–natural product interaction, given tify patients at risk of drug interactions is use of a screening
that these products can be a complex mixture of active phy- tool such as the Drug-Associated Risk Tool (DART). The DART
tochemicals (Fasinu 2012). Clinical pharmacists can help is a validated instrument consisting of 27 risk factors for
increase the knowledge base for potential drug–natural prod- developing drug-related problems. The DART is basically a
uct interactions by asking patients about their use of natural patient questionnaire that contains queries regarding health
products and reporting any unexpected adverse events. status, medications, and adherence. Investigators conducted
a prospective validation study of DART in 195 hospitalized
Box 1. Principles of Judicious
adults on orthopedic, geriatric, and internal medicine units
Prescribing
in Switzerland (Kaufmann 2018). These patients completed
• Think beyond drugs
the questionnaire, and answers were compared with objec-
○ Seek nondrug alternative therapeutic options initially
tive patient data from medical records and laboratory results.
○ Consider potentially treating the underlying cause of a
health issue rather than prescribing a drug for symptom Results showed that DART was associated with a satisfying
management feasibility and reliability, with the specificity of statements
○ Look for prevention opportunities instead of focusing on included in the questionnaire mostly high. The sensitivity of
treating symptoms or advanced disease DART varied, with higher sensitivity in statements related to
○ Use the test of time as a diagnostic and therapeutic disease states requiring ongoing monitoring and attention to
trial, when possible, instead of reflexively prescribing a
medication management. Overall, the authors concluded that
medication
querying patients regarding medications and related prob-
• Practice more strategic prescribing
○ Use only a few drugs and learn to use them well lems provides an uncomplicated rapid method of identifying
○ Avoid frequent changing to newly approved medications those who may be at increased risk of drug-related problems,
without clear, compelling evidence-based reasons including drug interactions, allowing clinical pharmacists to
○ Be skeptical about “individualizing” therapy, which can target interventions to patients who may benefit the most.
often be a code word for “trial and error” medicine
○ When possible, initiate therapy with only one drug at a Comprehensive Medication Management
time
Comprehensive medication management is the “standard
• Maintain heightened vigilance regarding adverse effects
of care that ensures each patient’s medications are individ-
○ Have a high index of suspicion for adverse drug effects
○ Educate patients about possible adverse effects to ually assessed to determine that each medication is appro-
ensure early recognition priate for the patient, effective for the medical condition, safe
○ Be alert to clues that you may be treating or risking given the comorbidities and other medications being taken,
withdrawal symptoms and able to be taken by the patient as intended” (ACCP 2021).
• Exercise caution and skepticism regarding new drugs Obtaining a medication history as part of CMM is fundamen-
○ Educate yourself about new drugs and indications from
tal for preventing adverse reactions caused by drug inter-
trustworthy, unbiased sources
actions, and one approach for clinical pharmacists to recall
○ Do not rush to use newly marketed drugs
○ Be certain that the drug improves actual patient-centered components of an appropriate history is to use the “AVOID
clinical outcomes rather than a surrogate marker Mistakes” mnemonic (Box 2) (FDA 2018).
○ Be vigilant about indications creep With respect to allergies, patients should be asked whether
○ Do not be seduced by elegant molecular pharmacology any medication should be avoided for any reason rather than
or drug physiology simply asking whether a drug allergy exists. If a patient
○ Beware of selective reporting of studies
• Work with patients for a shared agenda
○ Do not hastily or uncritically succumb to patient re-
quests for drugs, especially advertised medications Box 2. The “AVOID Mistakes” Mnemonic
○ Avoid mistakenly prescribing additional drugs to patients for Obtaining a Medication History
with refractory symptoms, failing to appreciate the • Allergies
potential for patient nonadherence ○ Identification of medications that should not be
○ Avoid repeating prescriptions for drugs that a patient prescribed for any reason
has previously tried unsuccessfully or that caused an • Vitamins
adverse reaction ○ Including natural products or herbs
○ Discontinue drugs that are not working or are no longer • Old and new medications
needed ○ Including prescription and OTC medications
○ Work with patients’ desires to be conservative with • Interactions
medications ○ Initial assessment of potential interactions
• Consider long-term, broader impacts • Dependence
○ Think beyond short-term beneficial effects to longer-term ○ Consider the need for a behavioral contract in the case
benefit-risk of either drug dependence or adherence to a therapeutic
regimen
○ Look for opportunities to improve prescribing systems in
order to improve prescribing and make medication use • Mendel
○ Family history of beneficial or negative outcomes with
safer
medications
Information from: Schiff GD, Galanter WL, Duhig J, et al.
Principles of conservative prescribing. JAMA 2011;171:1433-40. Information from: FDA. Preventable Adverse Drug Reactions:
A Focus on Drug Interactions.
indicates an “allergy” is present, follow-up questions regard- are at increased risk of medication-related harm because of
ing associated symptoms should be used to delineate the drug interactions and that clinical pharmacist interventions
severity of the reaction. Specific questions regarding natu- (e.g., pharmacist-led protocols and prescriptive authority)
ral product (e.g., vitamins, herbs, supplements) use should have a significant positive impact (Kasper 2020).
be asked because patients often do not consider these prod- Hand in hand with polypharmacy in the CMM process is
ucts as medications that might be subject to interactions. All the concept of deprescribing (Farrell 2019; Bemben 2016;
prescription and OTC medications should be accounted for, Garfinkel 2015; Scott 2015). Deprescribing refers to the sys-
including recently discontinued medications because some tematic identification, adjustment, and/or discontinuation of
agents have relatively long-lasting effects. A unique aspect medications when existing or potential harms of medications
of the mnemonic is identification of patients with drug depen- outweigh benefits within the context of an individual patient’s
dence or adherence issues, with the potential for establishing care goals, current level of functioning, life expectancy, val-
a behavioral contract to help the patient attain therapeu- ues, and preferences (Farrell 2019; Scott 2015). Deprescrib-
tic goals. Finally, questioning the patient regarding familial ing is not a mechanism to deny effective treatment to eligible
responses to relevant medications, whether positive or nega- patients; rather, it is an essential component of the prescrib-
tive, may determine whether a pharmacogenetic intervention ing continuum. Clinical pharmacists can engage in depre-
is necessary in order to tailor drug therapy and avoid harmful scribing as a means to prevent and manage drug interactions.
effects of a drug interaction. The deprescribing process involves (1) obtaining a complete
After obtaining a complete medication history, clinical medication list and determining an indication for each medi-
pharmacists may target patients who are prescribed sev- cation; (2) assessing each medication with respect to poten-
eral medications concurrently (i.e., polypharmacy) as a spe- tial for drug-related harm; (3) weighing the current or future
cific population of concern for drug interactions. Although no benefits against harms for each medication; (4) developing
standard definition of polypharmacy exists, it is often applied a plan to discontinue medications, with initial targets being
when patients are routinely administered five or more med- those with the highest burden and lowest benefit; and (5)
ications (WHO 2019). Polypharmacy is a major and growing discontinuing medications and monitoring for improvement
public health issue globally with negative consequences, in patient outcomes or the development of adverse effects
including reduced quality of life and increased risk of adverse (Bemben 2016; Scott 2015). Clinical pharmacists should con-
events, mortality, and health care use for patients; harmful sider deprescribing another means of preventing and manag-
effects on physician functionality and productivity; and pro- ing drug interactions in any older patient with a new symptom
liferation of medication errors (Halli-Tierney 2019; WHO 2019). suggestive of an adverse drug reaction; in those receiving
Many patient- and health care system–related risk factors high-risk medications or drug combinations; in those man-
for polypharmacy exist (Box 3). Clinical pharmacists should ifesting advanced or end-stage disease, dementia, extreme
be aware of these factors when executing CMM, given that frailty, terminal illness, or complete dependence on others
research has shown that patients experiencing polypharmacy for care; and in those administered preventive medications
for clinical situations associated with no increased disease
risk despite drug cessation (Scott 2015). Clinical pharmacists
Box 3. Risk Factors for Polypharmacy should also be aware of potential barriers to deprescribing,
Patient-related including clinical complexity, limited time for patient consul-
• Advanced age tation, fragmented care involving multiple prescribers, inade-
• Cognitive impairment quate information related to medication use (e.g., history of
• Developmental disability drug tolerance or indications for administration), ambiguous
• Frailty or changing goals of therapy, doubt about the benefits and
• Lack of a primary care physician
• Mental health issues harms of continuing or discontinuing specific medications,
• Several chronic medical conditions provider attitude that leans toward more rather than less drug
• Receiving care from several subspecialists use, fear of medication withdrawal effects, and pressure to
• Residency in a long-term care facility prescribe medications because of evidence-based practice
System-related guidelines and recommendations. Despite these barriers, a
• Inadequate transitions of care variety of point-of-care resources are available for clinical
• Poor medical recordkeeping pharmacists that can assist with successful deprescribing
• Prescription of medications in order to meet disease- as a tool for avoiding the potentially negative effects of drug
specific quality metrics
• Use of automated refill systems interactions (Table 2).
Information from: Halli-Tierney AD, Scarborough S, Carroll D. Communication and Patient Engagement
Polypharmacy: evaluating risks and deprescribing. Am Fam
Physician 2019;100:32-8. When counseling patients regarding the potential for drug
interactions, clinical pharmacists should encourage patients
Table 2. Deprescribing Resources
Resources General Resource Comments Specific Deprescribing Impact
American Geriatric Society Clinical pharmacists can use • Beers Criteria: List of medications that pose the
Beers Criteria these resources at the point highest harm to older adult patients; provides potential
MedStopper of care to identify potentially alternatives to reduce risk
STOPP/START criteria inappropriate medications • MedStopper: Sequences a patient’s medications from
“more likely to stop” to “less likely to stop” according to
the drug’s potential to improve symptoms and reduce the
risk of future illness and its likelihood of causing harm;
tapering recommendations are also provided, if needed
• STOPP/START criteria: Tool used to review potentially
inappropriate medications in older adults; application of
these criteria may improve medication appropriateness,
reduce polypharmacy and adverse drug reactions, and
lower medication costs
Deprescribing.org: These resources can help the • This website contains evidence-based deprescribing
Guidelines and algorithms clinical pharmacist engage guidelines and informational pamphlets for PPIs, antihy-
Informational pamphlets patients regarding deprescribing perglycemics, antipsychotics, benzodiazepine receptor
Shared decision-making in and determining potential agonists, and cholinesterase inhibitors and memantine.
deprescribing deprescribing options and In addition, the site contains a process guide for improving
provide ongoing support and shared decision-making with patients regarding medica-
monitoring tion management in long-term care facilities
Information from: Halli-Tierney AD, Scarborough S, Carroll D. Polypharmacy: evaluating risks and deprescribing. Am Fam Physician
2019;100:32-8; Farrell B, Mangin D. Deprescribing is an essential part of good prescribing. Am Fam Physician 2019;99:7-9.
to always read labels carefully and learn about any warnings web-based application that provides a full-text search of
or major drug interactions associated with their medications FDA-approved product labeling documents for prescription
(FDA 2008). Clinical pharmacists should explain to patients drugs and biological products, OTC medications, and animal
that there are varying types of drug interactions (e.g., drug- drug products. This application contains the Drug Facts label
drug; drug-food; drug-condition; drug-laboratory) and that information for over 87,000 human OTC drugs as of Decem-
interactions may result in differing effects, including a reduc- ber 30, 2020 (FDA 2021). Clinical pharmacists can use the
tion in therapeutic efficacy of a medication, unexpected Drug Facts label information as a quick resource to determine
adverse effects, an increase in the action of a particular drug, what drug interaction-related information is available on an
and potentially beneficial effects on a disease state (FDA OTC label and supplement this information for the patient as
2004). To promote safe medication use and reduce the poten- necessary.
tial for harmful effects related to drug interactions, patients
should be advised to store medications in their original con- DRUG INTERACTION RESOURCES
tainer for easy identification; visit a single pharmacy location Many general and specialty tertiary resources are available
for all medication-related needs; maintain a listing of all cur- to help clinical pharmacists evaluate and manage drug inter-
rent and recently discontinued prescription, OTC, and natu- actions. These resources may discuss the mechanism of
ral products; and inform all health care providers about all the interaction, rate its significance (including likelihood of
medicinal products they may be taking (FDA 2008). Encour- occurrence) and severity, discuss factors that may increase
aging patients to ask questions about potential signs of a risk, explain the quality and clinical relevance of the pri-
drug interaction, useful patient-friendly resources, and any mary literature supporting the interaction, and provide rec-
prescription and OTC medications, natural products, food ommendations for management. Some of these resources
products, and beverages that may need to be avoided when are freely available in various formats or exist as a compo-
initiating a new medication is also essential. nent of a subscription database (e.g., Clinical Pharmacology,
Over-the-counter medications are of particular concern Facts and Comparisons). This chapter primarily focuses on
because they are easily acquired by patients, and the nonpre- the drug interaction resources available in electronic formats
scription Drug Facts label has either limited or nonexistent and does not describe in depth those that may be available
information on drug interactions. The FDA has developed a in print format. Clinical pharmacists should be aware that all
Patient Care Scenario
A 75-year-old man with hypertension, heart failure, type 2 states that he “generally feels good” except he seems “not
diabetes, and chronic kidney disease comes to your med- to remember a lot of stuff” lately. You are concerned that
ication therapy management clinic with his daughter for this patient may be at increased risk of drug interactions
his initial visit and brings his medications. These include and want to intervene to prevent any negative adverse
a daily aspirin, enalapril, metoprolol, hydrochlorothiazide, effects. Explain why this patient may be at an increased
furosemide, glyburide, and ibuprofen. He also mentions drug interaction risk and steps you could take to prevent a
that he takes some natural products; however, he did not potential interaction.
bring them and cannot recall their names currently. He
ANSWER
Any patient with a medication regimen containing more prescription, OTC, and natural product use—including
than one drug or natural product is at risk of develop- dosage regimens and duration of use, medication his-
ing a drug interaction. However, older adult patients who tory (including discontinued products), and allergies—to
are more likely to receive several medications for chronic achieve a more complete picture of his medication profile.
conditions are at higher risk. This patient is an older After obtaining a complete medication list, you should
adult, has several chronic disease states, and is experi- determine an indication for each product; assess each
encing polypharmacy, given that he is routinely receiving product for potential drug-related harm; weigh the current
five or more medications. All of these factors increase this or future benefits against harms for each product; develop
patient’s drug interaction risk. an appropriate plan for discontinuing medications, if nec-
There are a variety of steps that you could take to essary; and monitor the patient for improved outcomes
prevent a potential drug interaction beyond identifying or potential adverse effects if treatment discontinuation
high-risk patients. These include incorporating judi- occurs. You can use deprescribing resources at the point
cious prescribing concepts into patient care, obtaining of care, such as the Beers Criteria and the STOPP/START
a comprehensive medication history, and implement- criteria, to help identify potentially dangerous or ineffec-
ing deprescribing principles. For this patient, you can tive medications for this patient.
query him (or his daughter) further regarding his current
1. FDA. CDER Conversation: Evaluating the Risk of Drug-Drug Interactions. 2017.

2. WHO. Medication Safety in Polypharmacy. Technical Report. 2019.
3. Bemben NM. Deprescribing: an application to medication management in older adults. Pharmacotherapy 2016;36:774-80.
4. Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate polypharmacy. The process of deprescribing. JAMA Intern Med
2015;175:827-34.
tertiary resources have innate limitations, including the lag level (established, probable, suspected, possible, doubtful/
time associated with updating information, most notably for unknown), and onset (delayed or rapid). The Facts and Com-
those available in print formats only, and that information parisons resource provides a short description of the inter-
within a tertiary resource may be incomplete for various rea- action, its mechanism, and the management approach and
sons (e.g., space limitations, inadequate searches of the bio- discusses the primary literature evaluating the interaction
medical literature by the author). with references (if available).
Lexicomp contains the Lexi-Interact tool, which allows
Drug Interaction Tools in Tertiary References users to enter a single medication and observe all potential
Clinical pharmacists are often familiar with tertiary subscrip- interactions or enter several medications and run an inter-
tion databases if they work in health care settings that pro- action report (Lexicomp 2021). Patient allergy data can be
vide employees with access to support the optimal provision added, when appropriate, as well. Each interaction mono-
of patient care. Beyond the general drug information within graph is assigned a risk rating (A = no known interaction; B =
these resources, these databases contain specific drug inter- no action needed; C = monitor therapy; D = consider therapy
action tools. The Facts and Comparisons interaction tool modification; X = avoid combination), with the progression
allows clinical pharmacists to search for interactions involv- from A to X associated with an increased urgency for clini-
ing various drugs, allergies, and diseases/conditions (Facts cal intervention. The monograph also contains a summary
and Comparisons 2021). Results from a search provide an statement qualifying the nature of the interaction(s) and an
analysis of potential drug-allergy, drug-drug, drug-food, and indication of outcome severity and/or onset for an unman-
drug-alcohol interactions as well as data regarding preg- aged interaction. The severity of interaction may be classified
nancy and lactation concerns, precautions in certain patient as minor (effects tolerable in most situations; medical inter-
populations, and duplicate therapy, if existing. For a specific vention is not necessary), moderate (medical intervention is
DDI monograph, the Facts and Comparisons tool rates inter- necessary to manage effects of the interaction), and major
action severity (major, moderate, or minor), documentation (serious effects may occur with the interaction, including
death, hospitalization, permanent injury, or therapeutic fail- condition and/or require a therapy alteration), major (the
ure). Regarding onset, the tool classifies the time from inter- interaction is life threatening and/or requires medical inter-
action to occurrence of related adverse events as immediate vention), and contraindicated. A unique aspect of the Micro-
(0–12 hours), rapid (12–72 hours), or delayed (more than medex interaction report is a documentation rating system,
72 hours). Lexi-Interact also provides clinical pharmacists which ranges from excellent (the interaction is clearly estab-
with recommended action steps for preventing potential lished by results from controlled studies) to fair (available
interaction-related adverse outcomes and a brief referenced data for the interaction are poor) and unknown.
discussion of published literature on the documented or pre- With the increasing availability of natural products, clini-
sumed interaction. A unique aspect of Lexi-Interact is the use cal pharmacists need a reliable source of information specific
of “interacting category members.” This section lists all the for drug–natural product interactions. Natural Medicines (for-
medications within a specific interacting category and marks merly known as the Natural Medicines Comprehensive Data-
with an asterisk those that have specifically been identified base) contains such a tool (Natural Medicines 2021). The
in the published literature as being involved in an interaction. Natural Medicines interaction checker contains individual
Clinical Pharmacology contains a tool called the Drug natural products as well as brand products that contain sev-
Interaction Report (Clinical Pharmacology 2021). Within eral vitamins and herbs. Results from the interaction checker
this tool, clinical pharmacists can add various medications consist of an interaction rating, severity, likelihood of occur-
to a drug list and then perform an interaction search. Clin- rence, and level of evidence. The interaction rating is color
ical pharmacists can also check for alcohol, food, caffeine, coded and may be minor (chance of an interaction occurring
grapefruit juice, enteral feeding, and tobacco interactions is possible, and patients should be made aware of it), moder-
with medications, if necessary, and assess for duplicate ther- ate (the combination should be avoided or used with caution,
apy. The Drug Interaction Report itself classifies interactions and patients should be counseled regarding potential adverse
into various severity categories—level 1 (contraindicated; outcomes), or major (concurrent use is contraindicated, and
avoid concomitant use), level 2 (major; an intervention should patients should be advised to avoid the combination). The like-
be performed before the drugs are coadministered or at the lihood of the interaction occurring ranges from unlikely (the
time of initiation), level 3 (moderate; a preemptive interven- interaction has only been shown in animal or in vitro research)
tion is usually not necessary; however, patients should be to likely (well-controlled studies of humans have shown that
monitored closely and counseled regarding potential adverse the interaction occurs). Similar to other databases, the Nat-
effects), and level 4 (minor; a clinically significant interac- ural Medicines interaction checker also determines a sever-
tion does not usually occur with concomitant use). The find- ity level for the interaction: insignificant, mild, moderate, or
ings within the report are not as in depth as those in Facts high; however, in contrast to others, this checker also uses a
and Comparisons and Lexicomp, with the provision of a basic level of evidence that shows the types of evidence supporting
interaction summary statement and an unreferenced para- the occurrence of the interaction. The level of evidence key is
graph discussing the mechanism of the interaction and man- classified from A to D, with each level defined as follows:
agement approach. A novel aspect of the drug interaction
tool within Clinical Pharmacology is the ability to provide a
• A: high-quality randomized controlled trials and high-
quality meta-analyses/quantitative systematic reviews
professional- or consumer-focused report of an interaction,
• B: nonrandomized clinical trials, nonquantitative system-
with the consumer report written in patient language and atic reviews, lower-quality randomized controlled trials,
detailing potential interaction-related symptoms. clinical cohort and case-control studies, historical
Micromedex is a widely available database in hospital controls, and epidemiologic studies
settings; its drug interaction tool allows clinical pharma- • C: consensus and expert opinion
cists to enter several prescription, OTC, and natural prod- • D: anecdotal evidence, in vitro or animal studies, and
ucts; add allergy data, if necessary; and subsequently run a theoretical effects on the basis of pharmacology
drug interaction report (Micromedex 2021). The report itself Of note, the checker does not evaluate for the presence of
details information related to drug-drug, drug-allergy, drug- natural product–natural product interactions but only for the
food, drug-ethanol, drug-laboratory, drug-tobacco, drug-preg- existence of drug–natural product interactions.
nancy, and drug-lactation interactions. The interaction detail
is generally more thorough than that in other tools and Specialty Drug Interaction Resources
includes an overall warning statement, an overview of clin- Some tertiary resources specifically focus on the mecha-
ical management, a severity level, a documentation rating, nism, effects, prevention, and management of drug interac-
probable mechanism and time to onset of the interaction, and tions. These include Hansten and Horn’s Drug Interactions
a referenced summary and overview of the published litera- and Stockley’s Drug Interactions. Hansten and Horn wrote
ture of the interaction. Interaction severity categories include the well-known Drug Interactions, Analysis and Management
unknown, minor (the interaction has limited clinical effects), textbook, which used to be printed annually but is now out
moderate (the interaction may exacerbate the patient’s of print. Their website contains a variety of information on
current topics in drug interactions and clinical decision sup- The type and extent of information vary significantly within
port (CDS). Hansten and Horn, both pharmacists, are currently each resource, with Drugs.com providing a health care pro-
the authors of The Top 100 Drug Interactions: A Guide to Patient fessional–focused interaction report that contains the most
Management (Hansten 2019). The book’s 2019 edition con- thorough reference data on the mechanism and clinical man-
tains individual monographs for the top 100 interactions, with agement of the interaction. Gold Standard is also notable for
comments on the effects observed, management consider- its consumer focus and ability to check for interactions with
ations, and patient monitoring recommendations. In addition, caffeine, enteral feedings, ethanol, food, grapefruit juice, and
the text includes a table of CYP and transporter substrates, tobacco. Clinical pharmacists may find this open access site
inhibitors, and inducers; a section on the effects of antibiot- useful when describing the potential effects of an interaction
ics on warfarin; drug interactions with drugs that prolong the to patients. Clinical pharmacists should also be aware that
QTc interval; genetic polymorphisms of CYP enzymes; drug an interaction may not appear across all of these databases;
interactions with natural products; and a drug interaction it may thus be worth validating any interaction concerns
probability scale. A unique feature of this resource is use of by checking two databases if these are the only interaction
the Operational Classification (ORCA) system (Hansten 2001), checkers available.
which assigns drug interactions to categories on the basis of
management of the interaction as follows: Evaluation of Drug Interaction Resources
Class 1: Avoid combination (risk of combination outweighs Publications have evaluated, analyzed, and/or compared
benefit) drug interaction resources. Investigators completed a
Class 2: Usually avoid combination (use only under special cross-sectional study of seven drug information resources—
circumstances) Lexicomp, Micromedex, Clinical Pharmacology, Facts and
Comparisons, Stockley’s Drug Interactions, Drug Interactions
• Interactions for which there are clearly preferable alterna-
Analysis and Management (print version no longer avail-
tives to one or both drugs
able), and Drug Interaction Facts (print version no longer
• Interactions to avoid using an alternative drug or other
therapy unless the benefit is judged to outweigh the available) (Patel 2016). The authors analyzed the informa-
increased risk tion provided by these resources for 100 drug-drug (n=82)
and drug–dietary supplement (n=18) clinically relevant inter-
Class 3: Minimize risk (assess risk and take one or more of
actions. Two independent reviewers gathered mechanism,
the following actions, if needed)
severity, clinical effect, level of documentation, and course
• Consider alternatives: alternatives may be available that of action data (if available) from each of the seven resources
are less likely to interact using a common form. The reviewers also documented the
• Circumvent: take action to minimize the interaction (with- time required to locate and gather the necessary informa-
out avoiding combination) tion within the resource. Results showed that, compared
• Monitor: early detection can minimize the risk of an with all other resources, Lexicomp (97%), Clinical Pharmacol-
adverse outcome
ogy (97%), and Micromedex (93%) had higher scope scores
Class 4: No special precautions (risk of adverse outcomes (i.e., does the resource contain an entry for the interaction?;
appears small) p<0.05) for each comparison. Micromedex had a higher over-
Class 5: Ignore (evidence suggests the drugs do not interact) all completeness score than the other resources (p<0.01 for
Stockley’s Drug Interactions has been described as the most each comparison). Lexicomp, Facts and Comparisons, and
comprehensive and authoritative reference on drug interac- Drug Interaction Facts also had higher completeness scores
tions (Preston 2019). Stockley’s Drug Interactions is available than all the other resources (except for Micromedex) (p<0.05
as an annual textbook and online through Medicines com- for each comparison). Micromedex had higher consistency
plete with an interaction checker. The text includes interac- scores than all other resources (p<0.05 for each comparison).
tions between medications, natural products, foods, drinks, Lexicomp also had significantly higher consistency scores
and drugs of abuse, with each interaction monograph includ- than Clinical Pharmacology (p=0.021). All resources were
ing the mechanism and clinical evidence for the interaction, similar regarding time to locate and gather information on the
an evaluation of its clinical importance, guidance on manage- interactions.
ment, and references. The most recent edition of Stockley’s Investigators compared the ability of five common DDI
contains over 4800 interaction monographs. software programs (i.e., Lexicomp, Micromedex, iFacts [Drug
Interaction Facts], Medscape, and Epocrates) to detect clin-
Open Access Databases/Websites with Drug ically important interactions (Kheshti 2016). The accuracy
Interaction Checkers of these resources was assessed using 360 unknown inter-
Beyond subscription-based resources, there are several open action pairs (taken randomly from prescriptions) and 40
access databases and websites that clinical pharmacists known clinically important interaction pairs. Comprehen-
can use for information related to drug interactions (Table 3). siveness was assessed by identifying the presence of the
Table 3. Overview of Open Access Databases/Websites for Drug Interactions
Open Access
Resource Comments Interaction Example
Epocrates • Family of resources about drugs and Fluvoxamine + Theophylline

disease states available online and as a Monitor/modify treatment
mobile application Monitor theophylline concentrations; decrease theophylline
• Need to register online (for free) before to one-third the usual dose: combination may increase
gaining access theophylline concentrations; risk of toxicity (hepatic
• Tool: Interaction MultiCheck metabolism inhibited)
• Checks for interactions between up to
30 prescription or OTC products at a time
• Minimal information provided on the
interaction and its management
• Information is not referenced
Drugs.com • Online and mobile resource that provides Fluvoxamine + Theophylline

drug monographs, a drug identifier, and Major interaction: Generally avoid
news related to medication approvals or Coadministration with fluvoxamine may significantly increase
recalls; contains both a consumer and a the serum concentrations of theophylline and the associated
professional “edition” risk of toxicity. The mechanism is fluvoxamine inhibition
• Limitation: Each page of the site contains of theophylline metabolism by CYP1A2. Case reports and
commercial advertisements pharmacokinetic studies indicate that fluvoxamine 50–100
• Tool: Drug Interactions Checker mg/day can reduce the clearance of theophylline by 50%–
• More in-depth interaction information 70%, resulting in toxic theophylline concentrations and/or
is provided compared with Epocrates clinical toxicity in some patients. Two- to 4-fold increases
with respect to the mechanism of the in theophylline serum concentrations or systemic exposure
interaction and clinical management (AUC) and half-life have been reported, with onset of clinical
• Searches drug-drug, drug-food interactions toxicity as early as 2 or 3 days and typically within 1 wk
as well as therapeutic duplications of initiating fluvoxamine. Patients with liver dysfunction
and provides interaction information may be less susceptible to the interaction. In a study of
focused toward health care professionals 10 healthy subjects, 10 subjects with mild hepatic impairment
and consumers (can change between (Child-Pugh class A), and 10 subjects with severe hepatic
a professional and consumer drug impairment (Child-Pugh class C), fluvoxamine-induced
interaction report) inhibition of theophylline clearance was reduced from 62%
• Classifies the interaction severity as major, in healthy subjects to 52% and 12% in subjects with mild and
moderate, or minor severe cirrhosis, respectively. These differences may be the
• References for statements in the drug result of reduced hepatic uptake of fluvoxamine as well as
interaction summary are provided in the reduced hepatic expression of CYP1A2 in the cirrhotic liver
health care professional report
Management: Use of theophylline or its salts in combination
with fluvoxamine should generally be avoided. If
coadministration is required, a reduction in theophylline
dosage by one-half to two-thirds should be considered.
Pharmacologic response and serum concentrations should
be closely monitored after initiation, discontinuation, or
change of dosage of fluvoxamine, with the theophylline
dosage adjusted accordingly. Patients should be advised
to contact their physician if they experience signs and
symptoms suggestive of theophylline toxicity such as
nausea, vomiting, diarrhea, anorexia, headache, tremor,
irritability, confusion, insomnia, seizure, palpitation, and
arrhythmia. Other selective serotonin reuptake inhibitors
including citalopram, escitalopram, fluoxetine, paroxetine,
and sertraline do not significantly inhibit CYP1A2 and may be
safer alternatives in theophylline-treated patients
(continued)
Table 3. Overview of Open Access Databases/Websites for Drug Interactions (continued)
Open Access
Medscape • Online and mobile clinical resource that Fluvoxamine + Theophylline

provides clinicians with information on
Serious: Use alternative
diseases, procedures, and medications;
Fluvoxamine will increase the concentration or effect
the resource also contains formulary
of theophylline by affecting hepatic enzyme CYP1A2
information, medical calculators, and
metabolism. Avoid or use alternative drug
image collections of various disease states
• Tool: Drug Interaction Checker
• Searches for interactions involving
prescription and OTC medications and
supplements
• Provides an interaction severity
classification
• Minimal information is provided regarding
the interaction; information is not
referenced
WebMD • Online and mobile resource that contains Fluvoxamine + Theophylline

information on health, drugs and
Serious
supplements, living healthy, family and
Potential for serious interaction; regular monitoring by your
pregnancy, and medical news
physician required
Fluvoxamine oral will increase the concentration or effect of
• Checks for interactions between two or
theophylline oral by altering drug metabolism
more prescription and OTC medications
and supplements
• Interaction severity rating classification:
Don’t use together, serious, monitor
closely, minor
• Minimal information related to the
interaction provided; information is not
referenced
Gold • Online resource that evaluates potential Fluvoxamine + Theophylline
Standard prescription, OTC, herbal, and vitamin
Severity: High
products for interactions
Fluvoxamine can increase the amount of theophylline in the
• Tool: Drug Interactions
blood if you are taking either theophylline or aminophylline.
• Beyond drug interactions, the database
Adverse effects from theophylline, aminophylline may
checks for interactions with caffeine,
become worse. Too much theophylline or aminophylline
enteral feedings, ethanol, food, grapefruit
can cause nausea, nervousness, or sleeplessness and
juice, and tobacco
occasionally other effects like rapid heartbeat, tremor, or
• Links the interaction to the various brand
seizures. Notify your prescriber if any of these effects occur.
names of the products involved
Your prescriber may need to closely monitor the blood
• Includes an interaction severity
concentration of theophylline
classification of high, moderate, and low
• Information provided is in consumer
language; information is not referenced
• Interface is minimalist in nature and
somewhat clumsy to use
RxList • Online resource that is part of the WebMD Fluvoxamine + Theophylline

Consumer Network
Serious: Use alternative
(continued)
Table 3. Overview of Open Access Databases/Websites for Drug Interactions (continued)
Open Access
• Classifies drug interactions as Possible serious or life-threatening interaction. Monitor

contraindicated, serious, significant, or closely. Use alternatives, if available. Fluvoxamine oral will
minor increase the concentration or effect of theophylline oral by
• Introductory webpage contains an affecting hepatic/intestinal CYP3A4 metabolism
overview of drug interactions
• Contains a “patients and caregivers” and
“clinician explanation” of the interaction
• Minimal information related to the
interaction provided; information is not
referenced
Patient Care Scenario

A 65-year-old man presents to the ED with concerns of for hypertension. No other medications are on his medica-
muscle weakness, stiffness, and dark urine for the past tion list. Explain the process for determining whether the
day. He has a history of hyperlipidemia and has been patient’s adverse effects are because of a potential DDI,
prescribed atorvastatin 40 mg once daily for 2 years. and counsel him regarding what to be aware of regarding
Recently, the patient was initiated on verapamil therapy drug interactions.
ANSWER
If a drug interaction is suspected in this patient, there are Atorvastatin should be discontinued if the patient has
a variety of subscription and open access, general, and markedly elevated CPK concentrations or if severe myop-
specialty tertiary resources (e.g., Facts and Comparisons, athy/rhabdomyolysis is diagnosed or suspected. Because
Epocrates, Stockley’s Drug Interactions) that you can con- this patient appears to have symptoms of myopathy/
sult as a clinical pharmacist for further information. The rhabdomyolysis, discontinuation of atorvastatin in this
content within each resource varies; therefore, it is import- situation seems warranted.
ant to check at least two resources to collect as much When counseling a patient regarding drug interac-
information as possible before proposing a clinical inter- tions, clinical pharmacists should explain the varying
vention. The interaction checker in Facts and Comparisons types of interactions, encourage patients to read labels
states that atorvastatin/verapamil is a moderately severe carefully, be cognizant of warnings or major drug inter-
interaction with a delayed onset for potential adverse actions associated with their medications, and be aware
effects. Inhibition of CYP3A4 by verapamil may reduce that interactions may result in differing effects that are
the metabolic elimination of atorvastatin, leading to an not always negative. To reduce the potential for harmful
increase in atorvastatin concentrations and subsequent drug interaction–related outcomes, patients should also
muscle weakness and symptoms of rhabdomyolysis, as be advised to store medications in their original container
in this patient. The interaction checker concludes that for easy identification, visit a single pharmacy location for
the documentation level for this interaction is “probable,” all medication-related needs, maintain a listing of all cur-
with references provided to support its potential occur- rent and recently discontinued medications and natural
rence. The Epocrates Interaction Check provides minimal products, and inform every health care provider about all
information compared with Facts and Comparisons and medicinal products they may be taking. For this patient,
generally states that the combination may result in you should explain that adding verapamil for high blood
increased atorvastatin concentrations and subsequent pressure to the existing atorvastatin for high cholesterol
myotoxicity. Neither of these references provides rec- led to an increase in the amount of atorvastatin in his
ommendations for clinical management; however, the blood and the harmful effects he is experiencing. To avoid
drug interactions tool in Micromedex supplies such infor- these effects in the future, different medications may be
mation. Micromedex states that if coadministration of prescribed to treat his blood pressure and cholesterol
atorvastatin with verapamil is necessary, lower starting issues without the negative muscle effects.
and maintenance doses of atorvastatin may be required.
1. Facts and Comparisons [online database]. St. Louis: Wolters Kluwer, 2021.
2. Micromedex [online database]. Ann Arbor, MI: Truven Health Analytics, 2021.
3. FDA. Avoiding Drug Interactions. 2008.
4. FDA. Drug Interactions: What You Should Know. 2004.
following elements within the drug interaction monograph of CDS Tools for Drug Interactions
each resource: severity, onset, mechanism, level of interac- A chapter on drug interactions would not be complete with-
tion, documentation, management, clinical manifestations, out a brief mention of the CDS tools used widely in hospitals,
case discussion, related drugs, and reference availability. pharmacies, and other health care institutions. Because drug
A total score for each software program was calculated on interactions may result in patient harm, several electronic
the basis of the sum of accuracy (75% of the total score) prescribing and medication information systems include
and comprehensiveness (25% of the total score). Lexicomp interruptive alerts and non-interruptive information, either
and Epocrates had the highest accuracy scores, followed by during prescriber order entry or during dispensing/verifica-
Micromedex, Medscape, and iFacts. The most comprehen- tion, as forms of CDS to warn clinicians of potential interac-
sive resource was iFacts, followed by Lexicomp. Overall, Lex- tions (Tilson 2016). In addition, health care institutions may
icomp and Micromedex were determined to provide the most have access to more than one CDS tool with a drug interac-
complete, accurate, and user-friendly applications. tion checker; therefore, clinical pharmacists should be aware
Investigators compared the severity categorization of of the potential for information mismatch regarding drug
potential psychiatric DDIs provided by six drug interaction interactions from CDS tools within their institution.
databases (i.e., Clinical Pharmacology, Lexicomp, Microme- The Centers for Medicare & Medicaid Services guidelines
dex, Drugs.com, Medscape, and Epocrates) (Monteith 2019). for achieving meaningful use of electronic health records
The authors selected 100 drug interaction pairs for analysis; include drug interaction screening, emphasizing the impor-
67 pairs included a psychiatric and nonpsychiatric drug and tance of CDS in this arena. However, issues surrounding the
33 included two psychiatric medications. The existing cate- quality of drug interaction alerts and subsequent clinician
gory of each potential DDI provided by the six databases was frustration and alert overrides remain prevalent (Edrees 2020;
converted into five categories for analysis: severe (contrain- Poly 2020; Wong 2017; Bryant 2014). To address these con-
dicated), major, moderate, minor, and none. If more than one cerns, a workgroup was convened to develop recommenda-
category for the potential interaction was found for an inter- tions for selecting DDIs for CDS. Members of the workgroup
action pair, the more serious category was selected for clas- addressed four key questions (Table 4).
sification. Results showed that the overall percent agreement Beyond this workgroup, other recommendations focus-
regarding the severity categorization for the 100 potential ing on improving the usability of CDS drug interaction alerts
psychiatric drug interaction pairs was 66% and that categori- were published in 2015 (Payne 2015). The individuals involved
zation often differed among the drug interaction databases. in this workgroup achieved consensus through drafting rec-
The authors recommended that clinicians check more than ommendations, collecting verbal or written comments from
one drug interaction database in clinical practice because of workgroup members, and revising documents until no addi-
the differences observed among the databases. tional substantive comments were provided. This group
A systematic review of DDI software in clinical practice focused on addressing three key questions. (1) What, how,
evaluated the usability and appropriateness of various com- where, and when do we display decision support? (2) Should
mercially available electronic databases (Roblek 2015). presentation of DDI decision support vary by clinicians?
After performing a systematic literature search, 38 publica- (3) How should effectiveness of DDI decision support be
tions were included in the analysis, with most studies (n=26) measured?
using a single software for the evaluation of potential drug Similar to the prior workgroup, members of the 2015 group
interactions. Results showed that the most commonly used recommended that each DDI alert should include the drugs
DDI software in the studies was Micromedex, followed by involved, a seriousness category, clinical consequences (and
Facts and Comparisons and Lexicomp. Among studies that frequency), the mechanism of the interaction, contextual
compared a database with clinician assessment of a DDI, information/modifying factors, recommended actions to mit-
there was a large discrepancy in the number and relevance igate potential harm, and information on the underlying evi-
of detected interactions, with an overlap as low as 11% in dence for the interaction. The group also recommended that
some cases. alerts be presented with a consistent use of color, visual cues,
Overall, published evidence evaluating available drug inter- terminology, and brevity with minimal impact on clinician
action resources has generally found subscription-based workflow. In addition, the most critical information related to
databases such as Micromedex, Lexicomp, and Facts and the DDI alert should be presented on the top-level screen of
Comparisons to be fairly comprehensive in scope, with one the alert, with linked information accessible on demand as
analysis concluding that Lexicomp and Micromedex provided necessary, at the point of decision-making. Regarding the
the most complete, accurate, and user-friendly applications presentation of interaction decision support for various cli-
(Kheshti 2016). However, clinical pharmacists should check nicians, the workgroup recommended that general alert con-
more than one drug interaction database in practice, if possi- tent be consistent regardless of the clinician; however, the
ble, because differences in interaction severity, documenta- alert message may be altered on the basis of context or func-
tion, and management may occur among resources. tion of the health care professional (e.g., recommendations
Table 4. Recommendations for the Selection of DDIs for CDS Systems
Key Questions Recommendations
What process should be used • Form a national consensus expert panel to develop and maintain a standard set of
to develop and maintain a clinically relevant DDIs for CDS systems, with oversight by a national organization
standard set of DDIs? • Use a systematic process for assembling DDI evidence
• Grade recommendations for risk management
• Develop a web-based tool to solicit community feedback on recommendations
• Ensure periodic and timely updates of the standard DDI set
What information should be • Each DDI should include:

included in a knowledgebase ○ Severity classification
of standard DDIs? ○ Clinical consequences
○ Frequency of harm and exposure
○ Modifying factors
○ Mechanism of the interaction
○ Recommended actions, with strength of recommendation
○ Evidence, with quality ratings
Can/should a list of • Classifying an interaction as “contraindicated” should occur infrequently and should
contraindicated drug pairs be reserved for drug pairs where coadministration should not be permitted under any
be established? circumstances
How can DDI alerts be more • Health care institutions should convene an interdisciplinary committee to periodically
intelligently filtered? review commonly overridden alerts and suggest ways to either suppress alerts of minimal
value or change their presentation format
• Allow users to provide feedback on alerts as part of continuous quality improvement
• Do not indiscriminately “turn off” alerts
• Modifications to DDI alerts should be done cautiously, with careful evaluation to ensure
that patient safety is not compromised
• Strategies to actively monitor for signs of harm for patients receiving concurrent
medications that may result in a DDI should be incorporated into CDS systems
CDS = clinical decision support.

Information from: Tilson H, Hines LE, McEvoy G, et al. Recommendations for selecting drug-drug interactions for clinical decision
support. Am J Health Syst Pharm 2016;73:576-85.
Practice Points
Even though pharmacists are experts in managing DDIs • Remain cognizant of patient-specific factors that can
and are familiar with their underlying mechanisms, they enhance the risk of clinically relevant DDIs, such as
must stay abreast with research identifying other pharma- genetic polymorphisms, polypharmacy, or impaired
cokinetic considerations, such as the influence of genetic organ function.
polymorphisms on DDIs and strategies on how best to • Obtain comprehensive medication histories, including
treat patients with potential DDIs. Particularly important any OTC or herbal products, to provide a complete DDI
for patients, pharmacists should engage in CMM to eval- assessment.
uate a patient’s full medication profile and seek efforts • Evaluate strategies for mitigating DDIs, which may
not only to mitigate DDIs but also to find opportunities to include monitoring plans or alterations in dose when
deprescribe. avoiding interacting combinations is not feasible.
For DDIs, pharmacists should: • Consider deprescribing as a means to prevent and man-
• Understand the underlying mechanisms and clinical age drug interactions.
data supporting potential DDIs. The strength of evi- • Identify the general and specialty tertiary resources
dence should be scrutinized on whether it is supported available at a practice site to help evaluate and manage
by data showing clinically relevant outcomes. drug interactions and advocate for additional resources
if gaps are identified.
for prescribers may focus on monitoring values to order Farrell B, Mangin D. Deprescribing is an essential part of
regarding the interaction, whereas pharmacists may require good prescribing. Am Fam Physician 2019;99:7-9.
notification to ensure that monitoring orders were placed and Fasinu PS, Bouic PJ, Rosenkranz B. An overview of the
the results reviewed). The workgroup also recommended the evidence and mechanisms of herb-drug interactions.
formation of a professional group or trusted agency to stan- Front Pharmacol 2012;3:69.
dardize the collection and analysis of DDI decision support/
FDA. Drug Interactions: What You Should Know. 2004.
alert data submitted in a de-identified manner to a central
repository to help measure the effectiveness of drug interac- FDA. Avoiding Drug Interactions. 2008.
tion CDS tools. Alert override rates alone may not be a good
FDA. CDER Conversation: Evaluating the Risk of Drug-Drug
measure of effectiveness. Interactions. October 2017.
FDA. Preventable Adverse Drug Reactions: A Focus on Drug

CONCLUSION
Interactions. 2018.
Although the true prevalence of clinically relevant DDIs is diffi-
cult to define, clinical pharmacists should be aware of poten- FDA Center for Drug Evaluation and Research. Clinical Drug
Interaction Studies. Cytochrome P450 and Enzyme- and
tial mechanisms for interactions and apply available data to
Transporter-Mediated Drug Interactions. Guidance for
an individual scenario. Prevention of adverse events associ- Industry. January 2020a.
ated with DDIs requires a systematic approach that involves
applying concepts of judicious prescribing and CMM, imple- FDA Center for Drug Evaluation and Research. Clinical Drug
Interaction Studies. FDA, Center for Drug Evaluation and
menting deprescribing principles, identifying patient-specific
Research. In Vitro Drug Interaction Studies – Cytochrome
risk factors, and consulting DDI resources. P450 and Enzyme- And Transporter-Mediated Drug
Interactions. Guidance for Industry. January 2020b.
FDA. FDALabel: Full-Text Search of Drug Labeling. 2021.

REFERENCES
American College of Clinical Pharmacy (ACCP). Compre- Garfinkel D, Ilhan B, Bahat G. Routine deprescribing of
hensive Medication Management in Team-Based Care. chronic medications to combat polypharmacy. Ther Adv
Accessed July 9, 2021. Drug Saf 2015;6:212-33.
Bahar MA, Setiawan D, Hak E, et al. Pharmacogenetics of Gonzaga de Andrade Santos TN, Mendonça da Cruz Macieira
drug-drug interaction and drug-drug-gene interaction: G, Cardoso Sodré Alves BM, et al. Prevalence of clinically
a systematic review on CYP2C9, CYP2C19 and CYP2D6. manifested drug interactions in hospitalized patients:
Pharmacogenomics 2017;18:701-39. a systematic review and meta-analysis. PLoS One
2020;15:e0235353.
Bemben NM. Deprescribing: an application to medication
management in older adults. Pharmacotherapy 2016; Hales CM, Servais J, Martin CS, et al. Prescription Drug
36:774-80. Use Among Adults Aged 40–79 in the United States and
Canada. August 2019. Accessed July 9, 2021.
Bryant AD, Fletcher GS, Payne TH. Drug interaction alert
override rates in the meaningful use era. Appl Clin Inform Halli-Tierney AD, Scarborough S, Carroll D. Polypharmacy:
2014;5:802-13. evaluating risks and deprescribing. Am Fam Physician
2019;100:32-8.
Chang SH, Chou IJ, Yeh YH, et al. Association between use of
non-vitamin K oral anticoagulants with and without con- Hansten PD, Horn JR. The Top 100 Drug Interactions. A
current medications and risk of major bleeding in nonval- Guide to Patient Management, 20th ed. Dunedin, FL:
vular atrial fibrillation. JAMA 2017;318:1250-9. H&H Publishing, 2019.
Clinical Pharmacology [online database]. Tampa, FL: Hansten PD, Horn JR, Hazlet TK. ORCA: OpeRational
Elsevier, 2021. Accessed January 12, 2021. ClassificAtion of drug interactions. J Am Pharm Assoc
2001;41:161-5.
Dechanont S, Maphanta S, Butthum B, et al. Hospital admis-
sions/visits associated with drug-drug interactions: a sys- Kasper B, Erdel A, Tabaka C, et al. Analysis of pharmacist
tematic review and meta-analysis. Pharmacoepidemiol interventions used to resolve safety target of polyphar-
Drug Saf 2014;23:489-97. macy (STOP) drug interactions. Fed Pract 2020;36:348-50.
Edrees H, Amato MG, Wong A, et al. High-priority drug-drug Kaufmann CP, Stampfli D, Mory N, et al. Drug-Associated
interaction clinical decision support overrides in a newly Risk Tool: development and validation of a self-as-
implemented commercial computerized provider order- sessment questionnaire to screen for hospitalized
entry system: override appropriateness and adverse drug patients at risk for drug-related problems. BMJ Open
events. J Am Med Inform Assoc 2020;27:893-900. 2018;8:e0166610.
Facts and Comparisons [online database]. St. Louis: Wolters Kheshti R, Aalipour M, Namasi S. A comparison of five com-
Kluwer, 2021. Accessed January 7, 2021. mon drug-drug interaction software programs regarding
accuracy and comprehensiveness. J Res Pharm Pract Qato DM, Wilder J, Schumm LP, et al. Changes in prescription
2016;5:257-63. and over-the-counter medication and dietary supplement
use among older adults in the United States, 2005 vs 2011.
König J, Müller F, Fromm MF. Transporters and drug-drug JAMA Intern Med 2016;176:473-82.
interactions: important determinants of drug disposition
and effects. Pharmacol Rev 2013;65:944-66. Rashrash M, Schommer JC, Brown LM. Prevalence and pre-
dictors of herbal medicine use among adults in the United
Lexicomp [online database]. St. Louis: Wolters Kluwer, 2021. States. J Patient Exp 2017;4:108-13.
Accessed January 7, 2021.
Roblek T, Vaupotic T, Mrhar A, et al. Drug-drug interaction
Magro L, Moretti U, Leone R. Epidemiology and characteris- software in clinical practice: a systematic review. Eur J
tics of adverse drug reactions caused by drug-drug inter- Clin Pharmacol 2015;71:131-42.
actions. Expert Opin Drug Saf 2012;11:83-94.
Rombola L, Scuteri D, Marilisa S, et al. Pharmacokinetic
Malki MA, Pearson ER. Drug-drug-gene interactions and interactions between herbal medicines and drugs:
adverse drug reactions. Pharmacogenomics J 2020; their mechanisms and clinical relevance. Life (Basel)
20:355-66. 2020;10:106.
McFeely SJ, Ritchie TK, Yu J. Identification and evaluation of Roughead EE. Multidrug interactions: the current clinical
clinical substrates of organic anion-transporting polypep- and pharmacovigilance challenge. J Pharm Pract Res
tides 1B1 and 1B3. Clin Transl Sci 2019;12:379-87. 2015;45:138-9.
Micromedex [online database]. Ann Arbor, MI: Truven Health Schiff GD, Galanter WL, Duhig J, et al. Principles of conserva-
Analytics, 2021. Accessed January 12, 2021. tive prescribing. JAMA 2011;171:1433-40.
Monteith S, Glenn T. A comparison of potential psychiatric Scott IA, Hilmer SN, Reeve E, et al. Reducing inappropriate
drug interactions from six drug interaction database pro- polypharmacy. The process of deprescribing. JAMA Intern
grams. Psychiatry Res 2019;275:366-72. Med 2015;175:827-34.
Moura CS, Acurcio FA, Belo NO. Drug-drug interactions Tilson H, Hines LE, McEvoy G, et al. Recommendations for
associated with length of stay and cost of hospitalization. selecting drug-drug interactions for clinical decision sup-
J Pharm Sci 2009;12:266-72. port. Am J Health Syst Pharm 2016;73:576-85.
Natural Medicines [database online]. Stockton, CA: Ther- Wong A, Amato MG, Seger DL, et al. Evaluation of medica-
apeutic Research Facility, 2021. Accessed January 12, tion-related clinical decision support alert overrides in the
2021. intensive care unit. J Crit Care 2017;39:156-61.
Nguyen T, Liu X, Abuhashem W, et al. Quality of evidence World Health Organization (WHO). Medication Safety in Poly-
supporting major psychotropic drug-drug interaction pharmacy. Technical Report. 2019. Accessed January 6,
warnings: a systematic literature review. Pharmacother- 2021.
apy 2020;40:455-68.
Wysowski DK, Corken A, Gallo-Torres H, et al. Postmarket-
Patel RI, Beckett RD. Evaluation of resources for analyzing ing reports of QT prolongation and ventricular arrhyth-
drug interactions. J Med Libr Assoc 2016;104:290-5. mia in association with cisapride and Food and Drug
Payne TH, Hines LE, Chan RC, et al. Recommendations Administration regulatory actions. Am J Gastroenterol
to improve the usability of drug-drug interaction clin- 2001;96:1698-703.
ical decision support alerts. J Am Med Inform Assoc Zheng WY, Richardson LC, Li L, et al. Drug-drug interactions
2015;22:1243-50. and their harmful effects in hospitalised patients: a sys-
Poly TN, Islam M, Yan HC, et al. Appropriateness of overrid- tematic review and meta-analysis. Eur J Clin Pharmacol
den alerts in computerized physician order entry: system- 2018;74:15-27.
atic review. JMIR Med Inform 2020;8:e15653.
Preston CL. Stockley’s Drug Interactions, 12th ed. London:

Pharmaceutical Press, 2019.
Self-Assessment Questions
1. A pharmacist is tasked with estimating the prevalence 4. A transplant recipient taking cyclosporine has started
of realized drug-drug interactions (DDIs) within hospital- taking St. John’s wort. Which one of the following
ized patients at a tertiary health system. Over the past adverse effects is best to monitor for in this patient?
year, 3145 individual patient encounters are identified.
A. Increased triglycerides
Which one of the following would be the best approach
B. Renal toxicity
in collecting additional data to estimate the prevalence
C. Sexual dysfunction
of clinically relevant DDIs?
D. Transplant rejection
A. Screen patient medication profiles through
5. A pharmacist providing transition of care services
Micromedex to identify major interactions.
reviews a patient whose medical history is significant
B. Quantify the number of potential drug interaction
only for acute coronary syndrome and diabetes who was
alerts that appeared in the clinical decision support
recently discharged from the hospital after receiving per-
(CDS) system.
cutaneous coronary intervention. The patient’s current
C. Evaluate the adverse events reported and their
medication list consists of aspirin, clopidogrel, lisinopril,
relation to potential DDIs.
metformin, metoprolol, omeprazole, pioglitazone, and
D. Conduct a Drug-Associated Risk Tool (DART)
simvastatin. Which one of the following is best to recom-
evaluation for a representative set of the patient
mend for this patient to mitigate potential DDIs?
encounters.
A. Change clopidogrel to prasugrel.
2. Which one of the following scenarios best represents a
B. Discontinue omeprazole.
clinically relevant DDI?
C. Educate the patient on the potential for decreased
A. Patient recently prescribed oral prednisone currently symptoms of hyperglycemia.
taking metformin with no significant changes in D. Change pioglitazone to empagliflozin.
blood glucose concentrations
6. A pharmacist is involved in direct patient care at an out-
B. Patient taking furosemide who uses an intermittent
patient clinic where a newly hired provider routinely
albuterol inhaler for asthma symptoms
“individualizes” therapy through trial and error, particu-
C. Patient taking an antidepressant who experiences
larly with recently approved medications. The pharma-
diaphoresis and tremor after linezolid is initiated for
cist is concerned that this approach to prescribing may
an infection
increase the risk of medication errors, including drug
D. Patient taking omeprazole 20 mg daily who is
interactions, and plans to discuss the principles of judi-
given fluconazole, resulting in a 2-fold increase in
cious prescribing with the provider in order to improve
omeprazole AUC
the provider’s prescribing patterns. Which one of the fol-
3. A 45-year-old man takes atorvastatin 40 mg once daily lowing principles of judicious prescribing would be best
for hypercholesterolemia management. His medical for the pharmacist to prioritize in discussion with the
history also includes plaque psoriasis, which recently provider?
became unresponsive to usual systemic treatments. His
A. Think beyond drugs.
physician has prescribed cyclosporine, and the patient
B. Maintain heightened vigilance regarding adverse
presents the prescription to you at the pharmacy. You are
effects.
concerned about the potential for a DDI between atorvas-
C. Consider long-term, broader impacts.
tatin and cyclosporine. Which one of the following mon-
D. Practice more strategic prescribing.
itoring parameters would be best to recommend for this
patient if this combination is used?
A. Creatinine phosphokinase
B. Cyclosporine trough concentrations
C. Liver function tests
D. Serum creatinine
7. A provider at a long-term care facility has asked for the 10. K.W. is experiencing polypharmacy, which may increase
pharmacist’s assistance in identifying residents who her risk of drug interactions. The pharmacist obtains
may be at increased risk of drug interactions in order to a medication list and assesses each medication with
target interventions to the residents who may benefit the respect to potential harm. Which one of the following is
most. Which one of the following residents is most likely the best next step to take for K.W. in the deprescribing
to be at an increased risk of drug interactions? process?
A. Patient A, who has hypertension, diabetes, and A. Develop a plan to discontinue medications.
heart failure and receives several prescription B. Discontinue medications and monitor patient
medications for disease state management outcomes.
B. Patient B, who only takes an aspirin daily for C. Weigh the current or future benefits against the
cardiovascular prevention and gingko for memory harms for each medication.
C. Patient C, who currently takes simvastatin for D. Seek nondrug alternative therapeutic options for the
hyperlipidemia and various natural products to patient.
promote general health
11. A patient approaches the pharmacist with con-
D. Patient D, who recently had a broken leg and is
cerns related to a potential drug interaction between
receiving only intravenous morphine as needed for
amiodarone and warfarin. She is aware that an interac-
pain
tion may occur but wonders about the degree to which
documentation exists regarding the interaction. Which
Questions 8-10 pertain to the following case. one of the following resources would be best to con-
K.W., a 72-year-old woman, is referred to a pharmacist’s com- sult with respect to the documentation rating of the
prehensive medication management (CMM) clinic by her new interaction?
primary care provider. Her home drugs include enalapril, war-
A. Micromedex
farin, aspirin, paroxetine, simvastatin, and ezetimibe. On fur-
B. Facts and Comparisons
ther discussion, K.W. also admits starting garlic and turmeric
C. Clinical Pharmacology
a few days ago because she had read these supplements
D. Lexicomp
might be beneficial for her.
12. A physician stops you in the clinic to ask about open
8. Given her medication/natural product profile, which
access electronic resources for drug interactions. He is
one of the following potential drug interactions is most
interested in a resource that provides not only an interac-
important to monitor for in K.W.?
tion severity rating, description of the interaction mech-
A. Concurrent use of aspirin and enalapril, which could anism, and recommendations for clinical management
increase the effectiveness of enalapril and reduce for him, but also consumer-focused information that he
blood pressure. can potentially share with his patients. Which one of the
B. Concurrent use of warfarin with simvastatin, which following information sources is best to share with this
could increase bleeding risk. colleague?
C. Concurrent use of warfarin with ezetimibe, which
A. Epocrates
could decrease PT or INR.
B. Drugs.com
D. Concurrent use of warfarin and garlic, which could
C. Medscape
decrease the anticoagulant effects of warfarin.
D. WebMD
9. Because of her concurrent use of aspirin and paroxe-
tine, which one of the following is best to recommend for
K.W.?
A. No additional clinical management
B. Close monitoring for signs of bleeding
C. Changing aspirin to ibuprofen
D. Adding misoprostol
13. A nurse practitioner calls the pharmacy regarding a 15. A pharmacist is working with the clinical informatics
potential interaction between atorvastatin and cyclo- team to update CDS tools to address the recent FDA
sporine. You consult Hansten and Horn’s Top 100 Drug communication about serious, life-threatening respira-
Interactions and discover that cyclosporine is likely to tory depression with gabapentinoids, particularly with
increase systemic exposure to atorvastatin, which is a coadministration with other CNS depressants. Which
class 2 interaction using the ORCA system. Which one one of the following strategies would be best to use for
of the following is best to recommend for managing this DDI alerts to reduce this risk?
interaction?
A. Classify the interaction between gabapentin and
A. There is no need to avoid this combination; however, opioids as contraindicated.
monitor the patient closely for signs of myopathy. B. Include comprehensive, detailed information about
B. This combination should always be avoided because the interaction on the top-level screen of the alert.
the risks of therapy outweigh the benefits. C. Highlight the need to monitor for respiratory
C. This combination should generally be avoided and depression symptoms for alerts targeted to
used only under special circumstances; a careful prescribers.
risk-benefit analysis and consideration of alternative D. Track alert override rates of the message as the sole
drug therapies should inform the decision. measure of effectiveness.
D. There is no need to avoid this combination; however,
the prescriber can consider alternatives that are less
likely to interact, if desired.
14. A nurse approaches you in the hallway seeking your
advice. She works part-time in a neighborhood clinic
and wonders whether there is an easily accessible online
drug interaction resource that she can refer patients to
if they have interaction questions. Which one of the fol-
lowing would best provide this colleague with patient-
friendly information?
A. Gold Standard
B. Micromedex
C. WebMD
D. Epocrates

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Drug Interactions: Scientific and

Table 1. Overview of Common DDI Mechanisms

Category Type of Interaction Overview Example

Absorption Changes in GI pH Alterations in pH by one drug Decreased bioavailability of posaconazole oral

Adsorption, Drug binding another drug to Administration of antacids with tetracyclines

Changes in GI Changes in transit time Increased cyclosporine exposure when given

Modulation of Changes in absorption of a Induction of P-glycoprotein with rifampin leads

Distribution Protein binding Competition for binding Increased risk of supratherapeutic

Modulation of Changes in uptake of a drug Increased exposure of ritonavir in the CNS

Enzyme induction Increase in synthesis of an Decreased simvastatin concentrations when

Enzyme inhibition Inhibition of an isoenzyme Increased warfarin concentrations when

Category Type of Interaction Overview Example

Enterohepatic Enterohepatic recirculation is Cholestyramine reduces the enterohepatic

Antagonistic Drugs with opposite Blood glucose–lowering effects of antidiabetics

Uptake Drug or Drugs occupy receptors on Response to norepinephrine is greatly increased

Establishing Evidence for Drug Interactions Drug-Drug-Gene Interactions

Resources General Resource Comments Specific Deprescribing Impact

1. FDA. CDER Conversation: Evaluating the Risk of Drug-Drug Interactions. 2017.

Epocrates • Family of resources about drugs and Fluvoxamine + Theophylline

Drugs.com • Online and mobile resource that provides Fluvoxamine + Theophylline

Medscape • Online and mobile clinical resource that Fluvoxamine + Theophylline

WebMD • Online and mobile resource that contains Fluvoxamine + Theophylline

RxList • Online resource that is part of the WebMD Fluvoxamine + Theophylline

• Classifies drug interactions as Possible serious or life-threatening interaction. Monitor

Patient Care Scenario

Key Questions Recommendations

What information should be • Each DDI should include:

of standard DDIs? ○ Clinical consequences

○ Frequency of harm and exposure

○ Mechanism of the interaction

○ Recommended actions, with strength of recommendation

○ Evidence, with quality ratings

CDS = clinical decision support.

FDA. Preventable Adverse Drug Reactions: A Focus on Drug

FDA. FDALabel: Full-Text Search of Drug Labeling. 2021.

Preston CL. Stockley’s Drug Interactions, 12th ed. London:

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