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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...

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 PSAP 2021 Book 3 Chronic Conditions and Public Health 8 Drug Interactions: Scientific and Clinical Principles 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) PSAP 2021 Book 3 Chronic Conditions and Public Health 9 Drug Interactions: Scientific and Clinical Principles  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 PSAP 2021 Book 3 Chronic Conditions and Public Health 10 Drug Interactions: Scientific and Clinical Principles 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. PSAP 2021 Book 3 Chronic Conditions and Public Health 11 Drug Interactions: Scientific and Clinical Principles  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 PSAP 2021 Book 3 Chronic Conditions and Public Health 12 Drug Interactions: Scientific and Clinical Principles  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. PSAP 2021 Book 3 Chronic Conditions and Public Health 13 Drug Interactions: Scientific and Clinical Principles 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 PSAP 2021 Book 3 Chronic Conditions and Public Health 14 Drug Interactions: Scientific and Clinical Principles  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 PSAP 2021 Book 3 Chronic Conditions and Public Health 15 Drug Interactions: Scientific and Clinical Principles  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 PSAP 2021 Book 3 Chronic Conditions and Public Health 16 Drug Interactions: Scientific and Clinical Principles 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 PSAP 2021 Book 3 Chronic Conditions and Public Health 17 Drug Interactions: Scientific and Clinical Principles 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