A Minimum Representation of Potential Drug-Drug Interaction Knowledge and Evidence

Abstract

The purpose of this Community Group Report is to provide a technical and user-centered foundation for a minimum information model for information about potential drug-drug interactions. The Report provides non-ambiguous definitions for 10 core information items. It also provides 8 detailed best practice recommendations related to the 10 core information items. The definitions and recommendations are shown as both narrative and prototype JSON artifacts using 2 exemplar potential drug-drug interactions. Twelve user stories with related goals illustrate use cases for the information model. Adoption of the recommendations by developers of PDDI knowledge artifacts will improve the usefulness of the artifacts within clinical workflows. Intended downstream applications include clinical decision support, drug product label enhancement, cohort identification, and other activities relevant to protecting patients from harmful drug interactions.

A. Appendices

This section is non-normative.

A.1 Development Process

Toward the goal of developing such a model, a volunteer-based Task Force force was formed by the Health Care and Life Sciences Interest Group, an interest group that operates publicly through the World Wide Web Consortium (W3C). This Task Force has taken a user-centered design approach to designing the minimal information model through the a series of complementary activities:

Development of decision trees of more than a dozen PDDIs to represent using the new information model.
Creation of user stories and use cases that define the requirements for the minimum information model.
Definition of guidelines for knowledge representation

A.1.1 Decision Trees

A.1.1.1 Selecting PDDIs to implement using the minimum information model

Prior work by some members of the Task Force has sought to develop evidence-based clinical algorithms that consider a patient’s electronic health record information to provide a clinician with actionable information tailored to the patient’s specific context. ¹The algorithms are formulated as decision trees to provide concise information including the interaction description, the purported mechanism and possible effects, the evidence supporting the mechanism and effects along with citations listed in the footnotes. Two sample decision trees illustrating the management options can be found in the appendix (see Appendix DECISION TREES).

¹The initial decision trees were developed through the “Individualized Drug Interaction Alerts” AHRQ grant by Task Force members Dan Malone and John Horn, as well as Phil Hansten (AHRQ Project: R21-HS023826-01; Title: Individualized Drug Interaction Alerts; Authors: Daniel C. Malone, University of Arizona; John Horn, Philip Hansten, University of Washington).

The Task Force built on this prior work by selecting PDDIs to demonstrate the new minimum information model and then creating decision trees for each of the PDDIs that they selected. Task Force drug experts selected the PDDIs and identified contextual information/modifying factors that would warrant any of three different recommended actions - No special precautions, Assess risk and take action if necessary, and Use only if benefit outweighs risk. Draft decision trees were presented during sub-team monthly meetings for thorough discussion. Revisions were made iteratively until the group reached consensus on the presented drafts and finalized the decision trees.

The Task Force began with a discussion of how to select the PDDIs for developing decision trees. One option was to select the most serious PDDIs. However, it was noted that the seriousness of a PDDI depends a great deal on the patient characteristics context. This meant that it would be difficult to identify PDDIs that were considered the most serious in all clinical settings and for all patients. An alternative approach was to choose PDDIs that would allow the Task Force to demonstrate how the information model should be used when facing known issues with PDDI evidence and knowledge. Toward that aim, participants were requested to provide suggestions of PDDIs meeting at least one or more of the following criteria which follow from the aforementioned information categories suggested by attendees of the multi-stakeholder conference meetings/series mentioned in Section § 6. Background and use cases:

The interaction could (and should) be contextualized for specific patients or clinical circumstances.
The interaction applies at the drug class level.
The interaction does not apply at the drug class level.
The mechanism is known and is pharmacokinetic.
The mechanism is known and is pharmacodynamic.
The mechanism is poorly described, not well elucidated.
The evidence supporting the interaction is strong.
The evidence supporting the interaction is weak.
The frequency of exposure data is available.
The frequency of exposure data is not available.
The frequency of adverse event data is available.
The frequency of adverse event data is not available.
The recommended action is “monitor” or “take note”.
The recommended action is “avoid”.
The recommended action is “a clear alternative drug and dose”.

A.1.1.2 Decision Trees Created for the Minimum Information Model Domain Analysis

The Task Force force developed 14 PDDI decision trees detailing the steps taken in using the the minimal information model to describe PDDIS. These exemplars were chosen to represent questions identified by the Task Force force as potentially affecting the search and syntheses of PDDI information. The potential interactions and the information situations they were selected for are listed in Table 1. Value sets defining relevant drug classes and clinical consequences are given in § A.4 Value Sets to Support PDDI Examples.

Table 1

Exemplar potential drug-drug interactions	Drug or Drug Class 1	Drug or Drug Class 2	Explanation/Justification
Can (and should) be contextualized for specific patients or clinical circumstances	Tamoxifen	Paroxetine	Patients with extensive CYP2D6 status on paroxetine will derive no benefit from tamoxifen. (Status: completed, view at Zenodo).
	Potassium (KCL)	Potassium-sparing Diuretics	Combination has known patient-specific risk factors. (Status: completed, email HCLS CG to request)
Applies at the class level	Monoamine Oxidase Inhibitors (MAOIs)	Indirect Sympathomimetics	A class interaction involving all drugs in the class. (Status: completed, view at Zenodo).
Does not apply at the class level	Tyrosine Kinase Inhibitors	Proton Pump Inhibitors	Not all kinase inhibitors have pH dependent absorption. Imatinib, nilotinib, dasatinib, bosutinib, and ponatinib are BCR‐ABL tyrosine kinase inhibitors. Imatinib and ponatinib do not have a significant interaction due to pH dependent absorption with proton pump inhibitors, whereas nilotinib, dasatinib, and bosutinib do (Lexi‐comp and Micromedex). (Status: completed, view at Zenodo).
The mechanism is known and is pharmacokinetic	Warfarin	CYP2C9 Inhibitors (ie. Bactrim)	A CYP-mediated pharmacokinetic interaction. (Status: completed, view at Zenodo)
The mechanism is known and is pharmacokinetic	Digoxin	Cyclosporin	A transport protein (p-glycoprotein) mediated interaction. (Status: completed, email HCLS CG to request)
The mechanism is known and is pharmacodynamic	Epinephrine	Beta-Blockers	The interaction is different differentiates between selective and non-selective beta blockers. The clinical outcome is a; hypertensive crisis. (Status: completed, email HCLS CG to request)
The mechanism is not well elucidated/known	Warfarin	Ifosfamide/Etoposide	Drugs for treating cancers of the blood drugs. - Clinical effect is INR change buts no mention of what mechanism could be found. (Status: completed, view at Zenodo)
The evidence supporting the interaction is strong	Epinephrine	Beta-Blockers	Widely known interaction with considerable available evidence. (Status: completed, email HCLS CG to request)
The evidence supporting the interaction is strong	Simvastatin, Atorvastatin, Lovastatin	Clarithromycin	Widely known interaction with considerable available evidence. (Status: completed, view at Zenodo)
The evidence supporting the interaction is weak	Warfarin	Antibiotics for which it is uncertain if inhibition of CYP2C9 affects warfarin	Hard to find evidence for the interaction. (Status: completed, view at Zenodo)
The frequency of exposure data is available	Warfarin	Non-steroidal anti-inflammatory drugs (NSAIDs)	Paper by Malone et al. - National sample. (Status: completed, view at Zenodo).
The frequency of exposure data is not available	Simvastatin	Fluconazole	Based on literature search. (Status: completed, view at Zenodo).
The frequency of adverse event data is available	Spironolactone	Potassium supplements	Associated with Risk of hospitalization. (Status: completed, email HCLS CG to request)
The frequency of adverse event data is not available	Simvastatin	Fluconazole	Literature search did not find frequency of adverse event data. (Status: completed, view at Zenodo).
The recommended action is “monitor” or “take note”	Potassium (KCL)	Potassium-sparing Diuretics	See explanation above. (Status: completed, email HCLS CG to request)
The recommended action is “avoid”	Monoamine Oxidase Inhibitors (MAOIs)	Indirect Sympathomimetics	See explanation above. (Status: completed, view at Zenodo).
The recommended action is a clear alternative drug and dose	Simvastatin	Amiodarone	The target of a drug safety communication from a regulatory agency [fda-simvastatin-amiodarone]. (Status: completed, view at Zenodo).

A.1.1.2.1 Example PDDI:Warfarin + NSAIDs

Non-steroidal anti-inflammatory drugs (NSAIDs) have antiplatelet effects which increase the bleeding risk when combined with oral anticoagulants such as warfarin. The antiplatelet effect of NSAIDs lasts only as long as the NSAID is present in the circulation, unlike aspirin’s antiplatelet effect, which lasts for up to 2 weeks after aspirin is discontinued. NSAIDs also can cause peptic ulcers and most of the evidence for increased bleeding risk with NSAIDs plus warfarin is due to upper gastrointestinal bleeding (UGIB).

Figure 5 ¢ = No special precautions. n = Assess risk and take action if necessary. u = Use only if benefit outweighs risk. Originally developed through "Individualized Drug Interactions" (AHRQ Project R21-HS023826-01) by Task Force Members Daniel Malone, John Horn, and Philp Hansten.
**Footnotes:**

Topical diclofenac has relatively low systemic absorption; in one study a topical gel (16 g/day) produced about 6% of the absorption seen with systemic administration of 150 mg/day. A higher than recommended dose of topical gel (48 g/day) produced 20% of a systemic dose of diclofenac. The UK Summary of Product Characteristics for Voltarol Ophtha Multidose Eye Drops states, "No measurable levels of diclofenac could be found in humans after ocular application of diclofenac sodium eye drops". The FDA-approved SPL for Diclofenac Sodium Ophthalmic Solution 0.1% states, "Results from a bioavailability study established that plasma levels of diclofenac following ocular instillation of two drops of Diclofenac sodium ophthalmic solution, 0.1% to each eye were below the limit of quantification (10 ng/mL) over a 4-hour period. This study suggests that limited, if any, systemic absorption occurs with Diclofenac sodium ophthalmic solution".

If the NSAID is being used as an analgesic or antipyretic, it would be prudent to use an alternative such as acetaminophen. In some people, acetaminophen can increase the anticoagulant effect of warfarin, so monitor the INR if acetaminophen is used in doses over 2 g/day for a few days. For more severe pain consider short-term opioids in place of the NSAID.

Proton pump inhibitors and misoprostol may reduce the risk of UGIB in patients receiving NSAIDs and warfarin.

Patients with a history of UGIB or peptic ulcer may have an increased risk of UGIB from this interaction. The extent to which older age is an independent risk factor for UGIB due to these interactions is not firmly established, but UGIB in general is known to increase with age.

Both corticosteroids and aldosterone antagonists have been shown to substantially increase the risk of UGIB in patients on NSAIDs, with relative risks of 12.8 and 11 respectively compared to a risk of 4.3 with NSAIDs alone [masclee-2014]

A.1.1.2.2 Example PDDI: BCR-ABL Tyrosine Kinase Inhibitors (TKI) + Proton Pump Inhibitors (PPI)

BCR-ABL Tyrosine Kinase inhibitors bosutinib, dasatinib, imatinib, nilotinib, and ponatinib are indicated for Philadelphia chromosome-positive chronic myeloid leukemia. Ponatinib is only approved in T315I-positive patients. These TKIs demonstrate pH dependent absorption for oral administration which may result in decreased efficacy when given concomitantly with medications that increase gastric pH. Dasatinib area under the curve (AUC) is decreased when co-administered with antacids, H2 antagonists, and PPIs.² Bosutinib and nilotinib AUCs are decreased with concomitant PPIs but antacids and H2 antagonists may be considered if TKI is given 2 hours before the antacid/H2 antagonist.^3,4 However, for nilotinib a retrospective study has shown no difference in cytogenetic response rates for patients taking PPIs.⁵ Imatinib and ponatinib AUCs are not appreciably decreased by PPI co-administration.^6,7

Figure 6 ¢ = No special precautions. n = Assess risk and take action if necessary. u = Use only if benefit outweighs risk. Originally developed through "Addressing gaps in clinically useful evidence on drug-drug interactions" (R01LM011838) NIH Grant by Task Force Members Evan Draper, Daniel C. Malone, John Horn, and Philip Hansten.

**Footnotes:**

[sprycel-2015]

[bosulif-2015]

[tasigna-2015]

[yin-2012]

[iclusig-2016]

[egorin-2009]

A.2 User Stories

This section is non-normative.

A.2.1 Workflow for arriving at stories and goals

User stories and goals were developed in order to showcase how the PDDI minimum information model will support users. The Task Force began developing the Stakeholder Description document and the PDDI Minimum Information Model User Scenarios document in order to identify key users. These stakeholder descriptions and user scenarios were used as the basis for further brainstorming with the assistance of a user experience expert to develop a master list of tasks, users, information needs, information values, and barriers to drug-drug interaction based decision-making in a variety of situations. A core set of user types was selected for development of user stories based on the scope of the minimum information model.

To develop the user stories for the core user types, Task Force members created an initial information needs list and then was supplemented it with user interviews, interview transcripts collected as a part of a recently published manuscript on PDDI information needs of drug information compendium editors [romagnoli-2017], and the published literature. Where possible, user stories were based on PDDIs suggested by the Task Force’s PDDI experts. All user stories were reviewed during team meetings to solicit feedback and comments. Based on Task Force member suggestions, the user stories were edited to make them more clinically relevant, accurate and appropriate. Information model items were highlighted based on a color-coded key to indicate the minimum information model information item in question.

A.2.2 User stories for the minimum information model

The following user stories use the color-coding described in to represent core information items defined for the minimum information model. A table summarizing the information needs exposed by these use cases is also presented in Appendix § A.2.2.2 A set of user stories focused on medication reconciliation.

A.2.2.1 Color codes used in user stories

This section is non-normative.

The following table illustrates the colors used to describe user stories. Note that frequency of exposure is not addressed in any of the user stories.

	Clinical Consequences
	Evidence
	Recommended Actions
	Mechanism of Interaction
	Contextual Evidence/Modifying Factors
	Seriousness Rating
	Frequency of Harm
	Frequency of Exposure

A.2.2.2 A set of user stories focused on medication reconciliation

This section is non-normative.

A.2.2.2.1 Use Story 1: Hospital Pharmacist, Medication Reconciliation upon Admission

A PDDI with unknown modifying factors: Linezolid + SSRIs (sertraline)

Beth is a hospital pharmacist who is reviewing the medications in the physician admission order for Bill, an 85-year-old male dementia patient who was transferred from a skilled nursing facility to the hospital after being diagnosed with a vancomycin-resistant Enterococcus faecium (VRE) infection. At the nursing home, Bill was prescribed sertraline to treat depression. Beth receives an alert that linezolid, which is being considered to treat the VRE infection, has a potential interaction with the sertraline that Bill is currently taking. Linezolid is a weak monoamine oxidase inhibitor, and has been shown to increase the risk of serotonin syndrome when taken concurrently with an SSRI such as sertraline. Beth would like to know the risks and benefits of continuing the sertraline and adding on the linezolid, the potential seriousness of the interaction’s clinical consequence, and recommended management options, such as selecting an alternative medication or discontinuing the sertraline. She would like to see the current evidence behind the interaction, so that she can determine if Bill has an increased risk of serotonin syndrome. In order to gather this information, she reviews Bill’s history, lab results, and allergies from the health records faxed by his skilled nursing facility, as well as his medication list upon admission. She reviews Lexicomp™ and the hospital’s intranet resources for additional information, but is having trouble finding information that is relevant to Bill’s situation. She does a literature search using PubMed in order to try to locate information about the frequency of adverse events in due to this potential interaction in other patients like Bill, but she does not have access to all of the articles in the search results.

A.2.2.2.2 User Story 2: Hospital Pharmacist, Medication Reconciliation upon Discharge

A PDDI that can (and should) be contextualized for specific patients or clinical circumstances: KCL (potassium chloride) + K-sparing Diuretics (spironolactone)

Beth is reviewing the physician’s discharge order for Maria. Maria is a 72-year old woman who was admitted to the hospital with acute decompensated heart failure. While reviewing Maria’s medications, Beth sees that Maria is being discharged with spironolactone, a potassium-sparing diuretic that could potentially interact with the potassium chloride that Maria had been taking to treat low potassium levels. Spironolactone may increase potassium levels in Maria’s blood, leading to hyperkalemia. Beth reviews Maria’s electronic health record in order to view her lab results and her other medications. She sees that Maria is also taking the ACE inhibitor lisinopril for heart failure, and since ACE inhibitors can also increase potassium levels, Beth would like to know how much this modifying factor might increase Maria’s risk of hyperkalemia due to the interaction between potassium chloride and spironolactone. Beth would like to know how likely it is that Maria will experience hyperkalemia, how serious hyperkalemia may be, and how to manage the interaction, such as by discontinuing one of Maria’s medications. Beth reviews the hospital’s intranet, as well as Micromedex™, for recommendations. She would also like more information about the potassium chloride that Maria was taking as one of her home medications, so she will need to contact Maria’s community pharmacy in order to find out the strength of the medication and if the prescription was still current.

A.2.2.2.3 User Story 3: Consultant Pharmacist, Medication Reconciliation upon Readmission

A PDDI with a known, pharmacokinetic mechanism: Warfarin + 2C9 inhibitors (metronidazole)

Patrick is a nursing home consultant pharmacist who is reviewing the medications of a readmitted patient, Nancy. Nancy is a 78 year-old woman who is being transferred back to her skilled nursing facility after a hospital admission for a Clostridium difficile (C. diff) infection; prior to the hospital admission, she was prescribed warfarin at the skilled nursing facility for deep vein thrombosis (DVT) treatment. Based on the hospital discharge summary, it appears that Nancy was taken off of the warfarin at the hospital due to an increased INR, and returned to the skilled nursing facility without an order for warfarin. Patrick sees that a potential interaction may occur with the warfarin that Nancy had been prescribed prior to her hospitalization, and the metronidazole now used to treat her infection, since metronidazole is a CYP2C9 inhibitor and may increase the plasma concentration of warfarin. A clinical consequence of this interaction would be an increased INR leading to an increased risk of bleeding. Patrick would like to gather management recommendations for this interaction prior to contacting Nancy’s physician. He is interested in Nancy’s duration of therapy for both the warfarin and the metronidazole, her current risk factors for a DVT, and if she is indicated for prophylactic therapy. Patrick also wants to know if and when warfarin should be restarted, and at what dose, in order to reduce the risk of bleeding due to the interaction. He would also like to know if metronidazole is the best option to continue treating Nancy’s C. diff infection, or if there is an alternative option that may not interact with warfarin. To gather this information, he reviews Nancy’s previous INR values, medication list, and history. He also contacts the hospital to determine whether warfarin had been given at any point during Nancy’s stay, if the dosage had been adjusted, what other medications she was given, and if any of her other medications were discontinued. He reviews his company’s intranet resources for additional information about the interaction and possible evidence-based recommendations. Finally, Patrick is interested in the frequency of serious bleeding events in geriatric patients co-prescribed warfarin and metronidazole, and the literature surrounding the interaction.

A.2.2.3 Treatment Planning, Physician

This section is non-normative.

Simvastatin + Amiodarone

Kathleen is a physician who is treating a patient who has a ventricular arrhythmia. Kathleen would normally prescribe amiodarone for this particular patient, but he is being treated with simvastatin for dyslipidemia, and she knows that a potentially serious interaction may occur leading to rhabdomyolysis. Kathleen wants to know what the patient’s risk factors are for rhabdomyolysis, what the benefits and risks would be to switching him to an alternative statin, and if amiodarone is not the best option for this patient, what alternatives to amiodarone exist for this patient, and what the available evidence shows in terms of ventricular arrhythmia patient outcomes.

(Pediatrics) Fluoxetine + Ondansetron

Evelyn is a pediatric emergency medicine physician caring for an adolescent with a history of major depressive disorder treated with fluoxetine, who presents with acute onset of vomiting and diarrhea. Evelyn’s usual first-line antiemetic for acute gastroenteritis is ondansetron, but Evelyn knows that both fluoxetine and ondansetron are listed as QTc-prolonging medications. Evelyn would like to know the likelihood of clinically significant QTc prolongation due to a brief course of co-administration of fluoxetine and ondansetron, and if there is a recommendation for dose adjustment or an alternate antiemetic.

(Pediatrics) Azole antifungals + Tacrolimus

William is a pediatric hospitalist caring for a child with a history of liver transplant due to congenital liver disease, treated with tacrolimus to prevent organ rejection. The patient is admitted with a fever and starts broad anti-infective therapy, including vancomycin, piperacillin-tazobactam and fluconazole. William knows that azole antifungals can increase tacrolimus levels and wants to know if there is evidence to guide a decrease the patient’s tacrolimus dose to prevent tacrolimus toxicity. He additionally wants to know the mechanism of interaction to avoid further interacting medications.

A.2.2.4 Evaluation of Management Options for Drug-Drug Interactions, Physician

This section is non-normative.

Warfarin + Naproxen

Melissa is a family physician whose patient called because he is experiencing noticeable bruising. Melissa knows that the patient is taking warfarin, but he has not experienced bruising before. She asks if the patient has taken any new medications recently, and he mentions that he visited a pain clinic for his chronic back pain and they prescribed the NSAID naproxen. Melissa knows that NSAIDs can increase the risk of bleeding when taken with warfarin, and she wants to know the best way to manage this interaction.

A.2.2.5 Evaluation of Management Options for Drug-Drug Interactions, Pharmacist

This section is non-normative.

Atorvastatin + Clarithromycin

James is a community pharmacist reviewing an electronic prescription that just came in for clarithromycin; an alert in his pharmacy’s information system indicates that there is a potential interaction between the clarithromycin and the atorvastatin that the patient was prescribed a year ago by different physician. James calls the patient in order to discuss her medications; she tells him that she is taking the atorvastatin as prescribed, and cannot remember if she has ever taken clarithromycin in the past. In preparation for following up with the patient’s physician, James would like to know the likelihood of an adverse drug event such as rhabdomyolysis occurring due to a potential interaction and how serious the interaction could be. He would also like to know if monitoring would be appropriate for this patient, or if a dose adjustment or temporary discontinuation of one of the drugs would be best.

A.2.2.6 Screening for Drug-Drug Interactions, Nurse

This section is non-normative.

Glipizide + Lisinopril (Sulfonylureas + ACE Inhibitors)

Nancy is a licensed practice nurse who works in a skilled nursing facility. She has noticed that her patient is experiencing symptoms of hypoglycemia. She sees that the patient was recently prescribed lisinopril, and is wondering if it interacts with one of the five medications that she is taking. Nancy remembers reading about a potential interaction with the glipizide that the patient is currently taking. She would like to know if the patient’s symptoms are a possible consequence of an interaction between the glipizide and the lisinopril, or the lisinopril and one of the other medications that the patient is taking, and if so, what information she should pass along to the registered nurse in charge in order to help treat the patient.

A.2.2.7 Synthesis for Dissemination, Drug Compendium Editor

This section is non-normative.

Tyrosine Kinase Inhibitors + Proton Pump Inhibitors

Olivia is a drug compendium editor who is reviewing the available literature for the potential interaction between tyrosine kinase inhibitors and proton pump inhibitors. She would like to review the most recent literature available surrounding the interaction, and would like to compare it against the existing entry in her drug compendium. She would like to understand more about the mechanism of the interaction, whether it applies to all drugs within the classes, whether certain populations are at greater risk, and the types and strength of the evidence available. She would also like to learn more about recommended management options.

A.2.2.8 Synthesis for Dissemination, Librarian

This section is non-normative.

Michael is a librarian who works for the medication safety unit in a regulatory agency. He has graduate training in library and information science, and has a good understanding of medical reference sources. When he is asked to locate information about a potential drug-drug interaction, he wants to understand more about the terms used to describe the drugs so that he can develop search strategies to run daily, weekly, and monthly searches. He would like to find terms used to describe the specific drugs involved in the interaction, drug class concepts, clinical consequences of the interaction, and existing types of evidence of the interaction.

A.2.2.9 Synthesis for Dissemination, Clinical Decision Support Team - Systems Analyst & Content Specialist

This section is non-normative.

Richard is a systems analyst who is working with Joe, a content specialist, in order to design a new clinical information system which can provide personalized clinical knowledge and patient information for clinicians to improve healthcare quality. Richard is professionally trained in algorithms, databases, and programming. He also has some knowledge about electronic medical records. In order to help Richard design and implement the system, Joe would like to know about the evidence, clinical consequences, and mechanisms of interactions of potential drug-drug interactions so that he can develop rules for the most clinically relevant interactions. With that information, he can help Richard create linkages and designs algorithms based on electronic medical records. Joe can also help Richard prioritize what to display and how to display information or alerts for clinicians.

A.2.2.10 Out of scope user stories

This section is non-normative.

The following user stories were considered as outside of scope of the task of developing the PDDI minimum information model, since the goals of the user stories were to determine how healthcare providers use PDDI information in patient care, what PDDI resources healthcare providers use when making patient care decisions, and how those PDDI resources are developed.

Synthesis for Dissemination, Clinical Decision Support User Interface Designer
Synthesis for Dissemination, Data Scientist
Population Management, Pharmacoepidemiologist
Population Management, Insurance Companies
Population Management, P&T Committee (Formulary Development)
Population Management, Med Safety Department (Pharmaceutical Industry)
Passive Role, Patient

A.3 Definition of guidelines for knowledge representation

This section is non-normative.

A sub-team of the task force focused on setting the scope of knowledge representation for the minimum information model. A series of teleconferences bringing together domain experts, biomedical informatics specialists, and knowledge representation experts across the task force. Starting with a core set of questions, topics were discussed, arguments for different approaches were laid out and, agreement among the participants was sought. Besides the conversation during the teleconferences, participants had the opportunity to add comments and voice their opinion to the statements in the document. When the task force arrived at a consolidated version, the group voted by teleconference and through e-mail. The result of that vote was written into a draft document. The final version of the document was revised and written as Section § 4. Knowledge representation for the minimal information model of this document.

A.4 Value Sets to Support PDDI Examples

This section is non-normative.

A.4.1 Some Background on Concept Identification and 'Value Sets'

According to the National Library of Medicine, value sets are lists of codes and corresponding terms from standard clinical vocabularies (such as SNOMED CT®, RxNorm, LOINC® and others), that define clinical concepts to support effective and interoperable health information exchange.[NLM-vsac-2019] Value sets are also referred to as "concept sets". Figure 7 shows some of the terminology sources that provide codes useful for constructing values sets for information items in the PDDI information model. Value sets may be explicitly defined by containing a terminology code for each term in the value set concepts. They can also be intensionally defined using an algorithm that, when executed by a machine (or interpreted by a human), yields a set of such elements. An HL7 project related to PDDI decision support effort is currently underway within HL7. The work has produced a draft implementation guide that includes a specification for constructing value sets for the drugs included in a PDDI.[HL7-cds-PDDI-draft]

Figure 7 Sources of value sets for two of the core information items of PDDI. Identifiers may come from above mentioned code systems or other relevant terminologies. As is typical for value sets, version, original code system and the code system version are required. The National Library of Medicine's Value Set Authority Center is a public site commonly used to store individual value sets.

A.4.2 aldosterone antagonists and products containing an aldosterone receptor antagonist (RxNorm)

298869 - eplerenone
9997 - Spironolactone
351256 - eplerenone 25 MG Oral Tablet
351257 - eplerenone 50 MG Oral Tablet
198224 - Hydrochlorothiazide 25 MG / Spironolactone 25 MG Oral Tablet
198225 - Hydrochlorothiazide 50 MG / Spironolactone 50 MG Oral Tablet
198222 - Spironolactone 100 MG Oral Tablet
313096 - Spironolactone 25 MG Oral Tablet
198223 - Spironolactone 50 MG Oral Tablet

A.4.3 bosutinib (ATC)

L01XE14 - bosutinib

A.4.4 cerebral hemorrhage (ICD-10-CM)

I61.0 - Nontraumatic intracerebral hemorrhage in hemisphere, subcortical
I61.1 - Nontraumatic intracerebral hemorrhage in hemisphere, cortical
I61.2 - Nontraumatic intracerebral hemorrhage in hemisphere, unspecified
I61.3 - Nontraumatic intracerebral hemorrhage in brain stem
I61.4 - Nontraumatic intracerebral hemorrhage in cerebellum
I61.5 - Nontraumatic intracerebral hemorrhage, intraventricular
I61.6 - Nontraumatic intracerebral hemorrhage, multiple localized
I61.9 - Nontraumatic intracerebral hemorrhage, unspecified
P10.2 - Intraventricular hemorrhage due to birth injury
P10.4 - Tentorial tear due to birth injury
P52.0 - Intraventricular (nontraumatic) hemorrhage, grade 1, of newborn
P52.1 - Intraventricular (nontraumatic) hemorrhage, grade 2, of newborn
P52.2 - Intraventricular (nontraumatic) hemorrhage, grade 3 and grade 4, of newborn
P52.3 - Unspecified intraventricular (nontraumatic) hemorrhage of newborn
P52.4 - Intracerebral (nontraumatic) hemorrhage of newborn
P52.9 - Intracranial (nontraumatic) hemorrhage of newborn, unspecified

A.4.5 chronic myeloid leukemia (SNOMED-CT)

415287001 - Relapsing chronic myeloid leukemia
277589003 - Atypical chronic myeloid leukemia
277587001 - Juvenile chronic myeloid leukemia

A.4.6 dasatinib (ATC)

L01XE06 - dasatinib

A.4.7 upper gastrointestinal bleeding or peptic ulcer (ICD-10-CM)

k92.2 – Gastrointestinal hemorrhage, unspecified
k25.0 – Acute gastric ulcer with hemorrhage
k25.2 – Acute gastric ulcer with hemorrhage and perforation
k25.4 – Chronic or unspecified gastric ulcer with hemorrhage
k25.6 – Chronic or unspecified gastric ulcer with both hemorrhage and perforation
k26.0 – Acute duodenal ulcer with hemorrhage
k26.2 - Acute duodenal ulcer with hemorrhage and perforation
k26.4 – Chronic duodenal ulcer with hemorrhage
k26.6 – Chronic duodenal ulcer with hemorrhage and perforation
k27.0 – Acute peptic ulcer, site unspecified, with hemorrhage
k27.2 - Acute peptic ulcer, site unspecified, with hemorrhage and perforation
k27.4 – Chronic peptic ulcer, site unspecified, with hemorrhage
k27.6 – Chronic peptic ulcer, site unspecified, with hemorrhage and perforation
k28.0 – Acute gastrojejunel ulcer with hemorrhage
k28.2 - Acute gastrojejunel ulcer with hemorrhage and perforation
k28.4 – Chronic gastrojejunel ulcer with hemorrhage
k28.6 – Chronic Acute gastrojejunel ulcer with hemorrhage and perforation
k29.01 – Acute gastritis with bleeding
k29.31 – Chronic gastritis with bleeding
k29.41 – Chronic atrophic gastritis with bleeding
k29.51 – Unspecified chronic gastritis with bleeding
k29.61 – Other gastritis with bleeding
k29.71 – Gastritis, unspecified, with bleeding
k29.81 – Duodenitis with bleeding
k29.91 – Gastroduodenitis, unspecified, with bleeding
k31.811 – Angiodysplasia –of stomach and duodenum with bleeding
k31.82 – Dieulafoy lesion (hemorrhagic) of stomach and duodenum

A.4.8 imatinib (ATC)

L01XE01 - imatinib

A.4.9 intracranial hemorrhage (ICD-10-CM)

I62.0 - Nontraumatic subdural hemorrhage
I62.1 - Nontraumatic extradural hemorrhage
I62.9 - Nontraumatic intracranial hemorrhage, unspecified
I69.2 - Sequelae of other nontraumatic intracranial hemorrhage
P10.0 - Subdural hemorrhage due to birth injury
P10.1 - Cerebral hemorrhage due to birth injury
P10.2 - Intraventricular hemorrhage due to birth injury
P10.3 - Subarachnoid hemorrhage due to birth injury
P10.4 - Tentorial tear due to birth injury
P10.8 - Other intracranial lacerations and hemorrhages due to birth injury
P10.9 - Unspecified intracranial laceration and hemorrhage due to birth injury
P52.0 - Intraventricular (nontraumatic) hemorrhage, grade 1, of newborn
P52.1 - Intraventricular (nontraumatic) hemorrhage, grade 2, of newborn
P52.2 - Intraventricular (nontraumatic) hemorrhage, grade 3 and grade 4, of newborn
P52.3 - Unspecified intraventricular (nontraumatic) hemorrhage of newborn
P52.4 - Intracerebral (nontraumatic) hemorrhage of newborn
P52.5 - Subarachnoid (nontraumatic) hemorrhage of newborn
P52.6 - Cerebellar (nontraumatic) and posterior fossa hemorrhage of newborn
P52.8 - Other intracranial (nontraumatic) hemorrhages of newborn
P52.9 - Intracranial (nontraumatic) hemorrhage of newborn, unspecified
S06.5 - Traumatic subdural hemorrhage
S06.8 - Other specified intracranial injuries

A.4.10 misoprostol (RxNorm)

42331 -  Misoprostol

A.4.11 nilotinib (ATC)

L01XE08 - nilotinib

A.4.12 Systemic non-steroidal anti-inflammatory drugs (NSAIDs) (RxNorm)

1665675 - 1 ML Ketorolac Tromethamine 15 MG/ML Cartridge
860092 - 1 ML Ketorolac Tromethamine 15 MG/ML Injection
860113 - 1 ML Ketorolac Tromethamine 15 MG/ML Prefilled Syringe
1665679 - 1 ML Ketorolac Tromethamine 30 MG/ML Cartridge
1665461 - 1 ML Ketorolac Tromethamine 30 MG/ML Injection
860114 - 1 ML Ketorolac Tromethamine 30 MG/ML Prefilled Syringe
1367426 - 12 HR Naproxen sodium 220 MG / Pseudoephedrine Hydrochloride 120 MG Extended Release Oral Tablet
1665682 - 2 ML Ketorolac Tromethamine 30 MG/ML Cartridge
1665459 - 2 ML Ketorolac Tromethamine 30 MG/ML Injection
860115 - 2 ML Ketorolac Tromethamine 30 MG/ML Prefilled Syringe
855657 - 24 HR Diclofenac Sodium 100 MG Extended Release Oral Tablet
310245 - 24 HR Etodolac 400 MG Extended Release Oral Tablet
359500 - 24 HR Etodolac 500 MG Extended Release Oral Tablet
310247 - 24 HR Etodolac 600 MG Extended Release Oral Tablet
314059 - 24 HR Ketoprofen 100 MG Extended Release Oral Capsule
311230 - 24 HR Ketoprofen 150 MG Extended Release Oral Capsule
359697 - 24 HR Ketoprofen 200 MG Extended Release Oral Capsule
433845 - 24 HR Naproxen 1000 MG Extended Release Oral Tablet
1116320 - 24 HR Naproxen 375 MG Extended Release Oral Tablet
1116339 - 24 HR Naproxen 500 MG Extended Release Oral Tablet
1116349 - 24 HR Naproxen 750 MG Extended Release Oral Tablet
992420 - 8 ACTUAT Ketorolac Tromethamine 15.8 MG/ACTUAT Nasal Inhaler
205322 - celecoxib 100 MG Oral Capsule
205323 - celecoxib 200 MG Oral Capsule
349514 - celecoxib 400 MG Oral Capsule
686379 - celecoxib 50 MG Oral Capsule
1297390 - Chlorpheniramine Maleate 2 MG / Ibuprofen 200 MG / Pseudoephedrine Hydrochloride 30 MG Oral Tablet
1310503 - Chlorpheniramine Maleate 4 MG / Ibuprofen 200 MG / Phenylephrine Hydrochloride 10 MG Oral Tablet
1442116 - Diclofenac 18 MG Oral Capsule
1442128 - Diclofenac 35 MG Oral Capsule
859063 - Diclofenac Potassium 1.67 MG/ML Oral Solution
858342 - Diclofenac Potassium 25 MG Oral Capsule
857702 - Diclofenac Potassium 25 MG Oral Tablet
855942 - Diclofenac Potassium 50 MG Oral Tablet
1234493 - Diclofenac Sodium 100 MG Oral Capsule
857696 - Diclofenac Sodium 100 MG Rectal Suppository
857698 - Diclofenac Sodium 12.5 MG Rectal Suppository
855664 - Diclofenac Sodium 25 MG Delayed Release Oral Tablet
857703 - Diclofenac Sodium 25 MG Rectal Suppository
1599787 - Diclofenac Sodium 37.5 MG/ML Injectable Solution
857706 - Diclofenac Sodium 50 MG / Misoprostol 0.2 MG Oral Tablet
855906 - Diclofenac Sodium 50 MG Delayed Release Oral Tablet
857709 - Diclofenac Sodium 50 MG Rectal Suppository
1359105 - Diclofenac Sodium 75 MG / Misoprostol 0.2 MG Oral Tablet
855926 - Diclofenac Sodium 75 MG Delayed Release Oral Tablet
895664 - Diphenhydramine Citrate 38 MG / Ibuprofen 200 MG Oral Tablet
901814 - Diphenhydramine Hydrochloride 25 MG / Ibuprofen 200 MG Oral Capsule
1550957 - Diphenhydramine Hydrochloride 25 MG / Naproxen sodium 220 MG Oral Tablet
994005 - Esomeprazole 20 MG / Naproxen 375 MG Delayed Release Oral Tablet
994008 - Esomeprazole 20 MG / Naproxen 500 MG Delayed Release Oral Tablet
197684 - Etodolac 200 MG Oral Capsule
197685 - Etodolac 300 MG Oral Capsule
197686 - Etodolac 400 MG Oral Tablet
199390 - Etodolac 500 MG Oral Tablet
1100066 - Famotidine 26.6 MG / Ibuprofen 800 MG Oral Tablet
199740 - fenbufen 450 MG Oral Tablet
197694 - Fenoprofen 200 MG Oral Capsule
858116 - Fenoprofen 400 MG Oral Capsule
310291 - Fenoprofen 600 MG Oral Tablet
197724 - Flurbiprofen 100 MG Oral Tablet
199749 - Flurbiprofen 200 MG Extended Release Oral Capsule
197725 - Flurbiprofen 50 MG Oral Tablet
859315 - Hydrocodone Bitartrate 10 MG / Ibuprofen 200 MG Oral Tablet
858770 - Hydrocodone Bitartrate 2.5 MG / Ibuprofen 200 MG Oral Tablet
858778 - Hydrocodone Bitartrate 5 MG / Ibuprofen 200 MG Oral Tablet
858798 - Hydrocodone Bitartrate 7.5 MG / Ibuprofen 200 MG Oral Tablet
310963 - Ibuprofen 100 MG Chewable Tablet
198405 - Ibuprofen 100 MG Oral Tablet
854183 - Ibuprofen 100 MG/ML Injectable Solution
1310487 - Ibuprofen 20 MG/ML / Pseudoephedrine Hydrochloride 3 MG/ML Oral Suspension
197803 - Ibuprofen 20 MG/ML Oral Suspension
1369775 - Ibuprofen 200 MG / Phenylephrine Hydrochloride 10 MG Oral Tablet
1299018 - Ibuprofen 200 MG / Pseudoephedrine Hydrochloride 30 MG Oral Capsule
1299021 - Ibuprofen 200 MG / Pseudoephedrine Hydrochloride 30 MG Oral Tablet
310964 - Ibuprofen 200 MG Oral Capsule
310965 - Ibuprofen 200 MG Oral Tablet
204442 - Ibuprofen 40 MG/ML Oral Suspension
1049589 - Ibuprofen 400 MG / Oxycodone Hydrochloride 5 MG Oral Tablet
197805 - Ibuprofen 400 MG Oral Tablet
197806 - Ibuprofen 600 MG Oral Tablet
197807 - Ibuprofen 800 MG Oral Tablet
346508 - Indomethacin 1 MG/ML Injectable Solution
199549 - Indomethacin 100 MG Rectal Suppository
1490727 - Indomethacin 20 MG Oral Capsule
197817 - Indomethacin 25 MG Oral Capsule
1491529 - Indomethacin 40 MG Oral Capsule
310991 - Indomethacin 5 MG/ML Oral Suspension
197818 - Indomethacin 50 MG Oral Capsule
197819 - Indomethacin 50 MG Rectal Suppository
310992 - Indomethacin 75 MG Extended Release Oral Capsule
199321 - Ketoprofen 100 MG Oral Capsule
249482 - Ketoprofen 100 MG Oral Tablet
199553 - Ketoprofen 100 MG Rectal Suppository
431823 - Ketoprofen 150 MG Extended Release Oral Tablet
429192 - Ketoprofen 25 MG Oral Tablet
197855 - Ketoprofen 50 MG Oral Capsule
247630 - Ketoprofen 50 MG Rectal Suppository
197856 - Ketoprofen 75 MG Oral Capsule
834022 - Ketorolac Tromethamine 10 MG Oral Tablet
860096 - Ketorolac Tromethamine 30 MG/ML Injectable Solution
618552 - Meclofenamate 100 MG Oral Capsule
618557 - Meclofenamate 50 MG Oral Capsule
597406 - meloxicam 1.5 MG/ML Oral Suspension
152695 - meloxicam 15 MG Oral Tablet
311486 - meloxicam 7.5 MG Oral Tablet
311892 - nabumetone 500 MG Oral Tablet
311893 - nabumetone 750 MG Oral Tablet
245420 - Naproxen 125 MG Oral Tablet
311913 - Naproxen 25 MG/ML Oral Suspension
198013 - Naproxen 250 MG Oral Tablet
603103 - Naproxen 375 MG Delayed Release Oral Tablet
198012 - Naproxen 375 MG Oral Tablet
311915 - Naproxen 500 MG Delayed Release Oral Tablet
198014 - Naproxen 500 MG Oral Tablet
199490 - Naproxen 500 MG Rectal Suppository
1112231 - Naproxen sodium 220 MG Oral Capsule
849574 - Naproxen sodium 220 MG Oral Tablet
849398 - Naproxen sodium 275 MG Oral Tablet
849450 - Naproxen sodium 500 MG / Sumatriptan 85 MG Oral Tablet
849431 - Naproxen sodium 550 MG Oral Tablet
1653765 - Naproxen sodium 60 MG / Sumatriptan 10 MG Oral Tablet
312132 - oxaprozin 600 MG Oral Tablet
198107 - Piroxicam 10 MG Oral Capsule
199559 - Piroxicam 10 MG Oral Tablet
247066 - Piroxicam 10 MG Rectal Suppository
198108 - Piroxicam 20 MG Oral Capsule
199560 - Piroxicam 20 MG Oral Tablet
105942 - Piroxicam 20 MG Rectal Suppository
199279 - Sulindac 100 MG Oral Tablet
198238 - Sulindac 150 MG Oral Tablet
198239 - Sulindac 200 MG Oral Tablet
199516 - tenoxicam 10 MG Oral Tablet
105954 - tenoxicam 20 MG Oral Tablet
250197 - tenoxicam 20 MG Rectal Suppository
198295 - Tolmetin 200 MG Oral Tablet
198296 - Tolmetin 400 MG Oral Capsule
198297 - Tolmetin 600 MG Oral Tablet
349319 - valdecoxib 10 MG Oral Tablet
349321 - valdecoxib 20 MG Oral Tablet

A.4.13 ponatinib (ATC)

L01XE24 - ponatinib

A.4.14 proton pump inhibitor (ATC)

A02BC06 - dexlansoprazole
A02BC05 - esomeprazole
A02BC03 - lansoprazole
A02BC01 - omeprazole
A02BC02 - pantoprazole
A02BC04 - rabeprazole

A.4.15 proton pump inhibitor (RxNorm)

816346 -  Dexlansoprazole
283742 -   Esomeprazole
17128 -  Lansoprazole
7646 -  Omeprazole
40790 -  Pantoprazole
114979 -  Rabeprazole

A.4.16 systemic corticosteroids (RxNorm)

1514 - Betamethasone
2878 - Cortisone
3264 - Dexamethasone
4452 - Fludrocortisone
5492 - Hydrocortisone
6902 - Methylprednisolone
8638 - prednisolone
8640 - Prednisone
10759 - Triamcinolone
1085795 - 100 ACTUAT Triamcinolone Acetonide 0.055 MG/ACTUAT Nasal Inhaler
833245 - 120 ACTUAT Triamcinolone Acetonide 0.05 MG/ACTUAT Nasal Inhaler
1085798 - 120 ACTUAT Triamcinolone Acetonide 0.055 MG/ACTUAT Nasal Inhaler
1493473 - 60 ACTUAT Triamcinolone Acetonide 0.055 MG/ACTUAT Nasal Inhaler
670084 - Betamethasone 0.12 MG/ML Oral Solution
308709 - Betamethasone 0.6 MG Oral Tablet
578803 - Betamethasone 3 MG/ML / Betamethasone acetate 3 MG/ML Injectable Suspension
197543 - Cortisone 10 MG Oral Tablet
197545 - Cortisone 5 MG Oral Tablet
828248 - cortisone acetate 25 MG Oral Tablet
309686 - Dexamethasone 0.1 MG/ML Oral Solution
197577 - Dexamethasone 0.5 MG Oral Tablet
854177 - Dexamethasone 0.7 MG Drug Implant
343033 - Dexamethasone 0.75 MG Oral Tablet
197579 - Dexamethasone 1 MG Oral Tablet
309684 - Dexamethasone 1 MG/ML Oral Solution
197580 - Dexamethasone 1.5 MG Oral Tablet
309696 - Dexamethasone 10 MG/ML Injectable Solution
197581 - Dexamethasone 2 MG Oral Tablet
197582 - Dexamethasone 4 MG Oral Tablet
197583 - Dexamethasone 6 MG Oral Tablet
1116927 - Dexamethasone phosphate 4 MG/ML Injectable Solution
313979 - Fludrocortisone 0.1 MG Oral Tablet
260192 - Hydrocortisone 0.01 MG/MG Rectal Ointment
310878 - Hydrocortisone 1.67 MG/ML Enema
197782 - Hydrocortisone 10 MG Oral Tablet
310868 - Hydrocortisone 10 MG/ML Rectal Cream
1494032 - Hydrocortisone 10 MG/ML Vaginal Cream
310899 - Hydrocortisone 2 MG/ML Oral Suspension
197783 - Hydrocortisone 20 MG Oral Tablet
1246528 - Hydrocortisone 25 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream
310879 - Hydrocortisone 25 MG/ML Rectal Cream
199320 - Hydrocortisone 4 MG Oral Tablet
197787 - Hydrocortisone 5 MG Oral Tablet
238755 - Hydrocortisone 50 MG/ML Injectable Solution
1012221 - hydrocortisone acetate 0.0055 MG/MG / Lidocaine Hydrochloride 0.028 MG/MG Rectal Gel
1012223 - hydrocortisone acetate 0.025 MG/MG / Lidocaine Hydrochloride 0.03 MG/MG Rectal Gel
1012229 - hydrocortisone acetate 10 MG/ML / Lidocaine Hydrochloride 30 MG/ML Rectal Cream
1235049 - hydrocortisone acetate 10 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream
828362 - hydrocortisone acetate 10 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Foam
1545172 - hydrocortisone acetate 100 MG/ML Rectal Foam
1114854 - hydrocortisone acetate 18.5 MG/ML / Pramoxine hydrochloride 11.5 MG/ML Rectal Cream
1012233 - hydrocortisone acetate 20 MG/ML / Lidocaine Hydrochloride 20 MG/ML Rectal Cream
1094443 - hydrocortisone acetate 23.5 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream
1291082 - hydrocortisone acetate 25 MG Rectal Suppository
1294025 - hydrocortisone acetate 25 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream
1291085 - hydrocortisone acetate 30 MG Rectal Suppository
1012235 - hydrocortisone acetate 5 MG/ML / Lidocaine Hydrochloride 30 MG/ML Rectal Cream
199771 - Methylprednisolone 100 MG Oral Tablet
328161 - Methylprednisolone 16 MG Oral Tablet
197969 - Methylprednisolone 2 MG Oral Tablet
197970 - Methylprednisolone 24 MG Oral Tablet
197971 - Methylprednisolone 32 MG Oral Tablet
259966 - Methylprednisolone 4 MG Oral Tablet
311659 - Methylprednisolone 40 MG/ML Injectable Solution
314099 - Methylprednisolone 62.5 MG/ML Injectable Solution
1357886 - Methylprednisolone 65.4 MG/ML Injectable Solution
197973 - Methylprednisolone 8 MG Oral Tablet
1358510 - methylprednisolone acetate 20 MG/ML Injectable Suspension
1358610 - methylprednisolone acetate 40 MG/ML Injectable Suspension
1358617 - methylprednisolone acetate 80 MG/ML Injectable Suspension
199343 - prednisolone 1 MG Oral Tablet
312614 - prednisolone 1 MG/ML Oral Solution
643123 - prednisolone 10 MG Disintegrating Oral Tablet
643125 - prednisolone 15 MG Disintegrating Oral Tablet
794979 - prednisolone 2 MG/ML Oral Solution
429199 - prednisolone 20 MG Oral Tablet
199967 - prednisolone 25 MG Oral Tablet
283077 - prednisolone 3 MG/ML Oral Solution
793099 - prednisolone 3 MG/ML Oral Suspension
643127 - prednisolone 30 MG Disintegrating Oral Tablet
702306 - prednisolone 4 MG/ML Oral Solution
198142 - prednisolone 5 MG Oral Tablet
249066 - prednisolone 5 MG/ML Oral Solution
1303125 - Prednisone 1 MG Delayed Release Oral Tablet
198144 - Prednisone 1 MG Oral Tablet
315187 - Prednisone 1 MG/ML Oral Solution
198145 - Prednisone 10 MG Oral Tablet
1303132 - Prednisone 2 MG Delayed Release Oral Tablet
198146 - Prednisone 2.5 MG Oral Tablet
312615 - Prednisone 20 MG Oral Tablet
1303135 - Prednisone 5 MG Delayed Release Oral Tablet
312617 - Prednisone 5 MG Oral Tablet
205301 - Prednisone 5 MG/ML Oral Solution
198148 - Prednisone 50 MG Oral Tablet
198301 - Triamcinolone 1 MG Oral Tablet
1085728 - Triamcinolone Acetonide 0.001 MG/MG Oral Paste
1085750 - Triamcinolone Acetonide 10 MG/ML Injectable Suspension
1085754 - Triamcinolone Acetonide 40 MG/ML Injectable Suspension
1085996 - triamcinolone hexacetonide 20 MG/ML Injectable Suspension
1085992 - triamcinolone hexacetonide 5 MG/ML Injectable Suspension

A.4.17 topical or opthalamic diclofenac (RxNorm)

1234735 - diclofenac epolamine 0.0129 MG/MG Topical Gel
854801 - Diclofenac Sodium Ophthalmic Solution

A.4.18 tyrosine kinase inhibitors (TKIs) (ATC)

L01XE04 - sunitinib
L01XC03 - trastuzumab
L01XC14 - ado-trastuzumab emtansine

A.4.19 warfarin (RxNorm)

855288 - Warfarin Sodium 1 MG Oral Tablet
855296 - Warfarin Sodium 10 MG Oral Tablet
855302 - Warfarin Sodium 2 MG Oral Tablet
855308 - Warfarin Sodium 2 MG/ML Injectable Solution
855312 - Warfarin Sodium 2.5 MG Oral Tablet
855318 - Warfarin Sodium 3 MG Oral Tablet
855324 - Warfarin Sodium 4 MG Oral Tablet
855332 - Warfarin Sodium 5 MG Oral Tablet
855338 - Warfarin Sodium 6 MG Oral Tablet
855344 - Warfarin Sodium 7.5 MG Oral Tablet
11289 - Warfarin

A.5 JSON Examples

This section is non-normative.

Here, we present prototype JSON documents for the two example PDDIs described in Section § 5. Examples of the use of the minimal information model. These examples should be considered informative (non-normative) and subject to revision.

Both of the examples below follow the recommendations provided in this Community Group Report. The examples are intended to show a simple approach to applying the recommendations to PDDIs using JSON, the Web Annotation Data Model [web-annotation-model], and BibJSON [bib-json].

An entirely different approach that is also compliant with the recommendations in this Report is the HL7 CDS Workgroup's draft Implementation Guide for PDDI CDS as a service [hl7-pddi-cds-ig-git]. The Implentation Guide integrates the PDDI minimum information model into PDDI CDS using the health information technology standards FHIR, Clinical Quality Language, and CDS Hooks.

The following non-normative conventions apply to the examples shown below:

The core information items are represented as key-value pairs.
The string labels of the core information items (e.g., "drugs involved", "clinical consequences", etc.) are the keys.
An identifier for the core information item class is provided in the "type" field of the value assocated with each infomation item. For example, the type of any value assigned to "clinical consequences" is "MPIO_0000003". A persistent URL can be constructed from each identifier by concatenating "http://purl.obolibrary.org/obo/" to the beginning of the identifier string (e.g., http://purl.obolibrary.org/obo/MPIO_0000003.
A unique URN identifier is used to identify each information item instance in the "id" field of the value assocated with each infomation item.
The "display" field of the value assocated with each infomation item shows human readable content relevant to the associated information item
There are many cases the unstructured text in a "display" field refers to an entity that is more clearly defined using a value set. In such cases, the value object has a "concept set references" field that holds a list of objects that can be used to unambiguously associate text mentions with concept sets. These objects use the Web Annotation Data Model [web-annotation-model] as follows:

The type of each object is a Web Annotation Data Model "TextQuoteSelector".
The value assigned to the Web Annotation Data Model "exact" field is used to indicate the specific text mention that is being mapped
The value assigned to the Web Annotation Data Model "body" field is an object that links the text mention to a concept set object provided within the JSON document. The concept set object is present in a list value assigned to the "concept sets" key within the same JSON document as the concept set reference. The the "value" field of the "body" of the concept set reference object holds the URN that uniquely identifies the specific concept set.

As an example, the following "clinical consequences" value has three concept set references for entities mentioned in the description. One for the mention of "gastrointestinal bleeding", one for the mention of "intracranial hemorrhage", and one for the mention of "cerebral hemorrhage". Each concept set reference object points to the exact value set using the URN assigned to the "value" field of the "body".

Example 1

"clinical consequences": {
"type": "MPIO_0000003",
"id": "5476c5b5-b52b-4750-882d-cc47f4fa52f4",
"display": "Increased risk of bleeding including gastrointestinal bleeding, intracranial hemorrhage, and cerebral hemorrhage",
"concept set references": [
{
       "type": "TextQuoteSelector",
       "exact": "gastrointestinal bleeding",
       "body": {
       "type": "SemanticTag",
       "value": "af3209ab-082f-40e6-9c37-6f2945afa850"
       }
},
{
       "type": "TextQuoteSelector",
       "exact": "intracranial hemorrhage",
       "body": {
       "type": "SemanticTag",
       "value": "2b083e55-755c-432a-9d78-ac5f55787737"
       }
},
{
       "type": "TextQuoteSelector",
       "exact": "cerebral hemorrhage",
       "body": {
       "type": "SemanticTag",
       "value": "5d5cf201-0a37-4c10-8397-da1aa774811e"
       }
}
]}

Whenever "evidence about a suspected drug-drug interaction" refers to a citable evidence item, a reference to that item is provided as BibJSON (a JSON version of BibTex) [bib-json]

A.5.1 Example 1: warfarin and systemic non-steroidal anti-inflammatory drugs (NSAIDs)

Example 2: Warfarin and systemic non-steroidal anti-inflammatory drugs (NSAIDs)

{
  "drugs involved": [
    {
      "type": "DIDEO_00000128",
      "id": "13d483d8-a955-49d1-af34-a762c6ad182c"
    },
    {
      "type": "DIDEO_00000128",
      "id": "7eecfe1a-073c-4af0-a14d-54b06d64455d"
    }
  ],
  "clinical consequences": {
    "type": "MPIO_0000003",
    "id": "5476c5b5-b52b-4750-882d-cc47f4fa52f4",
    "display": "Increased risk of bleeding including gastrointestinal bleeding, intracranial hemorrhage, and cerebral hemorrhage",
    "concept set references": [
      {
        "type": "TextQuoteSelector",
        "exact": "upper gastrointestinal bleeding",
        "body": {
          "type": "SemanticTag",
          "value": "af3209ab-082f-40e6-9c37-6f2945afa850"
        }
      },
      {
        "type": "TextQuoteSelector",
        "exact": "intracranial hemorrhage",
        "body": {
          "type": "SemanticTag",
          "value": "2b083e55-755c-432a-9d78-ac5f55787737"
        }
      },
      {
        "type": "TextQuoteSelector",
        "exact": "cerebral hemorrhage",
        "body": {
          "type": "SemanticTag",
          "value": "5d5cf201-0a37-4c10-8397-da1aa774811e"
        }
      }
    ]
  },
  "seriousness": {
    "type": "MPIO_0000009",
    "id": "06dea7b0-5cef-4587-86a2-54052a8d0457",
    "value": "serious",
    "display": "Bleeding is a serious potential clinical consequence because it can result in death, life-threatening hospitalization, and disability."
  },
  "mechanism of interaction information": {
    "type": "MPIO_0000005",
    "id": "8a8ce6c0-c78e-4d38-bda2-835118f976ea",
    "display": "Systemic non-steroidal anti-inflammatory drugs (NSAIDs) have antiplatelet effects which increase the bleeding risk when combined with oral anticoagulants such as warfarin. The antiplatelet effect of NSAIDs lasts only as long as the NSAID is present in the circulation, unlike aspirin's antiplatelet effect, which lasts for up to 2 weeks after aspirin is discontinued. NSAIDs also can cause peptic ulcers and most of the evidence for increased bleeding risk with NSAIDs plus warfarin is due to upper gastrointestinal bleeding (UGIB).",
    "concept set references": [
      {
        "type": "TextQuoteSelector",
        "attribute": "display",
        "exact": "Non-steroidal anti-inflammatory drugs (NSAIDs)",
        "body": {
          "type": "SemanticTag",
          "value": "7eecfe1a-073c-4af0-a14d-54b06d64455d"
        }
      },
      {
        "type": "TextQuoteSelector",
        "attribute": "display",
        "exact": "NSAIDs",
        "body": {
          "type": "SemanticTag",
          "value": "7eecfe1a-073c-4af0-a14d-54b06d64455d"
        }
      },
      {
        "type": "TextQuoteSelector",
        "attribute": "display",
        "exact": "warfarin",
        "body": {
          "type": "SemanticTag",
          "value": "13d483d8-a955-49d1-af34-a762c6ad182c"
        }
      }
    ]
  },
  "recommended action": {
    "type": "MPIO_0000008",
    "id": "b05ddcfe-c72a-4009-ad7e-c89221bb1ec7",
    "display": "If the NSAID is being used as an analgesic or antipyretic, it would be prudent to use an alternative such as acetaminophen. In some people, acetaminophen can increase the anticoagulant effect of warfarin, so monitor the INR if acetaminophen is used in doses over 2 g/day for a few days. For more severe pain consider short-term opioids in place of the NSAID."
  },
  "frequency of exposure to the PDDI": {
    "type": "MPIO_0000007",
    "id": "f8885290-1507-40a5-85cb-247756cb0064",
    "display": "Unknown"
  },
  "frequency of harm for persons who have been exposed to the PDDI": {
    "type": "MPIO_0000006",
    "id": "03853fb2-e398-42a0-a07b-a93141931bd4",
    "display": "Unknown"
  },
  "modifying factors information": {
    "type": "MPIO_0000000",
    "id": "56a7ba39-467b-42c7-b117-485fecacb91d",
    "expressionLogic": "human readable",
    "members": [
      {
        "display": "The NSAID is topical or ophthalmic diclofenac",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "No special precautions."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Topical diclofenac has relatively low systemic absorption; in one study a topical gel (16 g/day) produced about 6% of the absorption seen with systemic administration of 150 mg/day. A higher than recommended dose of topical gel (48 g/day) produced 20% of a systemic dose of diclofenac."
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "topical or ophthalmic diclofenac",
            "body": {
              "type": "SemanticTag",
              "value": "484ef188-5765-408d-b8c3-f2f38ae8066c"
            }
          }
        ]
      },
      {
        "display": "The NSAID is NOT topical diclofenac but the patient is concomitantly taking a proton pump inhibitor or misoprostol",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "Assess risk and take action if necessary."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Proton pump inhibitors and misoprostol may reduce the risk of UGIB in patients receiving NSAIDs and warfarin."
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "topical or ophthalmic diclofenac",
            "body": {
              "type": "SemanticTag",
              "value": "484ef188-5765-408d-b8c3-f2f38ae8066c"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "proton pump inhibitor",
            "body": {
              "type": "SemanticTag",
              "value": "818e9fed-e18d-45de-b900-1edbedee8c89"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "misoprostol",
            "body": {
              "type": "SemanticTag",
              "value": "ab5731f3-a127-4ce7-bfe8-cfcafd6e3b86"
            }
          }
        ]
      },
      {
        "display": "The NSAID is NOT topical diclofenac, the patient is NOT concomitantly taking a proton pump inhibitor or misoprostol, and the patient 1) has a history of upper gastrointestinal bleeding (UGIB) or peptic ulcer or 2) age > 65 years old",
        "type": "MPIO_0000111",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "Use only if benefit outweighs risk."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Patients with a history of UGIB or peptic ulcer may have an increased risk of UGIB from this interaction. The extent to which older age is an independent risk factor for UGIB due to these interactions is not firmly established, but UGIB in general is known to increase with age."
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "topical or ophthalmic diclofenac",
            "body": {
              "type": "SemanticTag",
              "value": "484ef188-5765-408d-b8c3-f2f38ae8066c"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "proton pump inhibitor",
            "body": {
              "type": "SemanticTag",
              "value": "818e9fed-e18d-45de-b900-1edbedee8c89"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "misoprostol",
            "body": {
              "type": "SemanticTag",
              "value": "ab5731f3-a127-4ce7-bfe8-cfcafd6e3b86"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "upper gastrointestinal bleeding (UGIB) or peptic ulcer",
            "body": {
              "type": "SemanticTag",
              "value": "6a085888-7bc2-4b6a-8547-95d635cbcb3a"
            }
          }
        ]
      },
      {
        "display": "The NSAID is NOT topical diclofenac, the patient is NOT concomitantly taking a proton pump inhibitor or misoprostol, and the patient is concomitantly taking systemic corticosteroids, aldosterone antagonists, or high dose or multiple NSAIDs",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "Use only if benefit outweighs risk."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Both corticosteroids and aldosterone antagonists have been shown to substantially increase the risk of UGIB in patients on NSAIDs, with relative risks of 12.8 and 11 respectively compared to a risk of 4.3 with NSAIDs alone [masclee-2014].",
          "References": [
            {
              "title": "Risk of upper gastrointestinal bleeding from different drug combinations",
              "author": [
                {
                  "name": "Gwen MC Masclee "
                },
                {
                  "name": "Vera E Valkhoff"
                },
                {
                  "name": "Preciosa M Coloma"
                },
                {
                  "name": "Maria de Ridder"
                },
                {
                  "name": "Silvana Romio"
                },
                {
                  "name": "Martijn J Schuemie"
                },
                {
                  "name": "Ron Herings"
                },
                {
                  "name": "Giampiero Mazzaglia"
                },
                {
                  "name": "Gino Picelli"
                },
                {
                  "name": "L Scotti"
                }
              ],
              "type": "article",
              "year": "2014",
              "journal": {
                "name": "Gastroenterology",
                "volume": "147",
                "number": "4",
                "pages": "784--792"
              },
              "link": [
                {
                  "url": "https://www.gastrojournal.org/article/S0016-5085%2814%2900768-9/fulltext"
                }
              ],
              "identifier": [
                {
                  "type": "doi",
                  "id": "10.1053/j.gastro.2014.06.007"
                }
              ]
            }
          ]
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "topical or ophthalmic diclofenac",
            "body": {
              "type": "SemanticTag",
              "value": "484ef188-5765-408d-b8c3-f2f38ae8066c"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "proton pump inhibitor",
            "body": {
              "type": "SemanticTag",
              "value": "818e9fed-e18d-45de-b900-1edbedee8c89"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "misoprostol",
            "body": {
              "type": "SemanticTag",
              "value": "ab5731f3-a127-4ce7-bfe8-cfcafd6e3b86"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "corticosteroids",
            "body": {
              "type": "SemanticTag",
              "value": "13d50375-4ad3-4d19-af8c-e13870b06907"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "aldosterone antagonists",
            "body": {
              "type": "SemanticTag",
              "value": "a32b4ed0-1aff-4520-a973-879f705a0366"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "systemic NSAIDs",
            "body": {
              "type": "SemanticTag",
              "value": "7eecfe1a-073c-4af0-a14d-54b06d64455d"
            }
          }
        ]
      }
    ]
  },
  "concept sets": [
    {
      "id": "13d483d8-a955-49d1-af34-a762c6ad182c",
      "display": "warfarin",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "code": "11289",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855288",
          "display": "Warfarin Sodium 1 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855296",
          "display": "Warfarin Sodium 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855302",
          "display": "Warfarin Sodium 2 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855308",
          "display": "Warfarin Sodium 2 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855312",
          "display": "Warfarin Sodium 2.5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855318",
          "display": "Warfarin Sodium 3 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855324",
          "display": "Warfarin Sodium 4 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855332",
          "display": "Warfarin Sodium 5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855338",
          "display": "Warfarin Sodium 6 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855344",
          "display": "Warfarin Sodium 7.5 MG Oral Tablet"
        }
      ]
    },
    {
      "id": "7eecfe1a-073c-4af0-a14d-54b06d64455d",
      "display": "Systemic anti-inflammatory agents, Non-Steroidal",
      "system": "http://www.nlm.nih.gov/research/umls/snomedct",
      "code": "C0003211",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1665675",
          "display": "1 ML Ketorolac Tromethamine 15 MG/ML Cartridge"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "860092",
          "display": "1 ML Ketorolac Tromethamine 15 MG/ML Injection"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "860113",
          "display": "1 ML Ketorolac Tromethamine 15 MG/ML Prefilled Syringe"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1665679",
          "display": "1 ML Ketorolac Tromethamine 30 MG/ML Cartridge"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1665461",
          "display": "1 ML Ketorolac Tromethamine 30 MG/ML Injection"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "860114",
          "display": "1 ML Ketorolac Tromethamine 30 MG/ML Prefilled Syringe"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1367426",
          "display": "12 HR Naproxen sodium 220 MG / Pseudoephedrine Hydrochloride 120 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1665682",
          "display": "2 ML Ketorolac Tromethamine 30 MG/ML Cartridge"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1665459",
          "display": "2 ML Ketorolac Tromethamine 30 MG/ML Injection"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "860115",
          "display": "2 ML Ketorolac Tromethamine 30 MG/ML Prefilled Syringe"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855657",
          "display": "24 HR Diclofenac Sodium 100 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310245",
          "display": "24 HR Etodolac 400 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "359500",
          "display": "24 HR Etodolac 500 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310247",
          "display": "24 HR Etodolac 600 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "314059",
          "display": "24 HR Ketoprofen 100 MG Extended Release Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311230",
          "display": "24 HR Ketoprofen 150 MG Extended Release Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "359697",
          "display": "24 HR Ketoprofen 200 MG Extended Release Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "433845",
          "display": "24 HR Naproxen 1000 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1116320",
          "display": "24 HR Naproxen 375 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1116339",
          "display": "24 HR Naproxen 500 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1116349",
          "display": "24 HR Naproxen 750 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "992420",
          "display": "8 ACTUAT Ketorolac Tromethamine 15.8 MG/ACTUAT Nasal Inhaler"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "205322",
          "display": "celecoxib 100 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "205323",
          "display": "celecoxib 200 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "349514",
          "display": "celecoxib 400 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "686379",
          "display": "celecoxib 50 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1297390",
          "display": "Chlorpheniramine Maleate 2 MG / Ibuprofen 200 MG / Pseudoephedrine Hydrochloride 30 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1310503",
          "display": "Chlorpheniramine Maleate 4 MG / Ibuprofen 200 MG / Phenylephrine Hydrochloride 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1442116",
          "display": "Diclofenac 18 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1442128",
          "display": "Diclofenac 35 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "859063",
          "display": "Diclofenac Potassium 1.67 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "858342",
          "display": "Diclofenac Potassium 25 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "857702",
          "display": "Diclofenac Potassium 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855942",
          "display": "Diclofenac Potassium 50 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1234493",
          "display": "Diclofenac Sodium 100 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "857696",
          "display": "Diclofenac Sodium 100 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "857698",
          "display": "Diclofenac Sodium 12.5 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855664",
          "display": "Diclofenac Sodium 25 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "857703",
          "display": "Diclofenac Sodium 25 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1599787",
          "display": "Diclofenac Sodium 37.5 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "857706",
          "display": "Diclofenac Sodium 50 MG / Misoprostol 0.2 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855906",
          "display": "Diclofenac Sodium 50 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "857709",
          "display": "Diclofenac Sodium 50 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1359105",
          "display": "Diclofenac Sodium 75 MG / Misoprostol 0.2 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "855926",
          "display": "Diclofenac Sodium 75 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "895664",
          "display": "Diphenhydramine Citrate 38 MG / Ibuprofen 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "901814",
          "display": "Diphenhydramine Hydrochloride 25 MG / Ibuprofen 200 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1550957",
          "display": "Diphenhydramine Hydrochloride 25 MG / Naproxen sodium 220 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "994005",
          "display": "Esomeprazole 20 MG / Naproxen 375 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "994008",
          "display": "Esomeprazole 20 MG / Naproxen 500 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197684",
          "display": "Etodolac 200 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197685",
          "display": "Etodolac 300 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197686",
          "display": "Etodolac 400 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199390",
          "display": "Etodolac 500 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1100066",
          "display": "Famotidine 26.6 MG / Ibuprofen 800 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199740",
          "display": "fenbufen 450 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197694",
          "display": "Fenoprofen 200 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "858116",
          "display": "Fenoprofen 400 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310291",
          "display": "Fenoprofen 600 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197724",
          "display": "Flurbiprofen 100 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199749",
          "display": "Flurbiprofen 200 MG Extended Release Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197725",
          "display": "Flurbiprofen 50 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "859315",
          "display": "Hydrocodone Bitartrate 10 MG / Ibuprofen 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "858770",
          "display": "Hydrocodone Bitartrate 2.5 MG / Ibuprofen 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "858778",
          "display": "Hydrocodone Bitartrate 5 MG / Ibuprofen 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "858798",
          "display": "Hydrocodone Bitartrate 7.5 MG / Ibuprofen 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310963",
          "display": "Ibuprofen 100 MG Chewable Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198405",
          "display": "Ibuprofen 100 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "854183",
          "display": "Ibuprofen 100 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1310487",
          "display": "Ibuprofen 20 MG/ML / Pseudoephedrine Hydrochloride 3 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197803",
          "display": "Ibuprofen 20 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1369775",
          "display": "Ibuprofen 200 MG / Phenylephrine Hydrochloride 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1299018",
          "display": "Ibuprofen 200 MG / Pseudoephedrine Hydrochloride 30 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1299021",
          "display": "Ibuprofen 200 MG / Pseudoephedrine Hydrochloride 30 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310964",
          "display": "Ibuprofen 200 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310965",
          "display": "Ibuprofen 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "204442",
          "display": "Ibuprofen 40 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1049589",
          "display": "Ibuprofen 400 MG / Oxycodone Hydrochloride 5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197805",
          "display": "Ibuprofen 400 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197806",
          "display": "Ibuprofen 600 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197807",
          "display": "Ibuprofen 800 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "346508",
          "display": "Indomethacin 1 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199549",
          "display": "Indomethacin 100 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1490727",
          "display": "Indomethacin 20 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197817",
          "display": "Indomethacin 25 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1491529",
          "display": "Indomethacin 40 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310991",
          "display": "Indomethacin 5 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197818",
          "display": "Indomethacin 50 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197819",
          "display": "Indomethacin 50 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310992",
          "display": "Indomethacin 75 MG Extended Release Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199321",
          "display": "Ketoprofen 100 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "249482",
          "display": "Ketoprofen 100 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199553",
          "display": "Ketoprofen 100 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "431823",
          "display": "Ketoprofen 150 MG Extended Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "429192",
          "display": "Ketoprofen 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197855",
          "display": "Ketoprofen 50 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "247630",
          "display": "Ketoprofen 50 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197856",
          "display": "Ketoprofen 75 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "834022",
          "display": "Ketorolac Tromethamine 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "860096",
          "display": "Ketorolac Tromethamine 30 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "618552",
          "display": "Meclofenamate 100 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "618557",
          "display": "Meclofenamate 50 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "597406",
          "display": "meloxicam 1.5 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "152695",
          "display": "meloxicam 15 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311486",
          "display": "meloxicam 7.5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311892",
          "display": "nabumetone 500 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311893",
          "display": "nabumetone 750 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "245420",
          "display": "Naproxen 125 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311913",
          "display": "Naproxen 25 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198013",
          "display": "Naproxen 250 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "603103",
          "display": "Naproxen 375 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198012",
          "display": "Naproxen 375 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311915",
          "display": "Naproxen 500 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198014",
          "display": "Naproxen 500 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199490",
          "display": "Naproxen 500 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1112231",
          "display": "Naproxen sodium 220 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "849574",
          "display": "Naproxen sodium 220 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "849398",
          "display": "Naproxen sodium 275 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "849450",
          "display": "Naproxen sodium 500 MG / Sumatriptan 85 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "849431",
          "display": "Naproxen sodium 550 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1653765",
          "display": "Naproxen sodium 60 MG / Sumatriptan 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "312132",
          "display": "oxaprozin 600 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198107",
          "display": "Piroxicam 10 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199559",
          "display": "Piroxicam 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "247066",
          "display": "Piroxicam 10 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198108",
          "display": "Piroxicam 20 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199560",
          "display": "Piroxicam 20 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "105942",
          "display": "Piroxicam 20 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199279",
          "display": "Sulindac 100 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198238",
          "display": "Sulindac 150 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198239",
          "display": "Sulindac 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199516",
          "display": "tenoxicam 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "105954",
          "display": "tenoxicam 20 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "250197",
          "display": "tenoxicam 20 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198295",
          "display": "Tolmetin 200 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198296",
          "display": "Tolmetin 400 MG Oral Capsule"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198297",
          "display": "Tolmetin 600 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "349319",
          "display": "valdecoxib 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "349321",
          "display": "valdecoxib 20 MG Oral Tablet"
        }
      ]
    },
    {
      "id": "af3209ab-082f-40e6-9c37-6f2945afa850",
      "display": "upper gastrointestinal bleeding",
      "type": "NCIT_C113497",
      "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
      "members": [
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k92.2",
          "display": "Gastrointestinal hemorrhage, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.0",
          "display": "Acute gastric ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.2",
          "display": "Acute gastric ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.4",
          "display": "Chronic or unspecified gastric ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.6",
          "display": "Chronic or unspecified gastric ulcer with both hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.0",
          "display": "Acute duodenal ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.2",
          "display": "Acute duodenal ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.4",
          "display": "Chronic duodenal ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.6",
          "display": "Chronic duodenal ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.0",
          "display": "Acute peptic ulcer, site unspecified, with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.2",
          "display": "Acute peptic ulcer, site unspecified, with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.4",
          "display": "Chronic peptic ulcer, site unspecified, with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.6",
          "display": "Chronic peptic ulcer, site unspecified, with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.0",
          "display": "Acute gastrojejunel ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.2",
          "display": "Acute gastrojejunel ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.4",
          "display": "Chronic gastrojejunel ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.6",
          "display": "Chronic Acute gastrojejunel ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.01",
          "display": "Acute gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.31",
          "display": "Chronic gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.41",
          "display": "Chronic atrophic gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.51",
          "display": "Unspecified chronic gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.61",
          "display": "Other gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.71",
          "display": "Gastritis, unspecified, with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.81",
          "display": "Duodenitis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.91",
          "display": "Gastroduodenitis, unspecified, with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k31.811",
          "display": "Angiodysplasia –of stomach and duodenum with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k31.82",
          "display": "Dieulafoy lesion (hemorrhagic) of stomach and duodenum"
        }
      ]
    },
    {
      "id": "6a085888-7bc2-4b6a-8547-95d635cbcb3a",
      "display": "upper gastrointestinal bleeding (UGIB) or peptic ulcer",
      "type": "NCIT_C113497",
      "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
      "members": [
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k92.2",
          "display": "Gastrointestinal hemorrhage, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.0",
          "display": "Acute gastric ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.2",
          "display": "Acute gastric ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.4",
          "display": "Chronic or unspecified gastric ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k25.6",
          "display": "Chronic or unspecified gastric ulcer with both hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.0",
          "display": "Acute duodenal ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.2",
          "display": "Acute duodenal ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.4",
          "display": "Chronic duodenal ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k26.6",
          "display": "Chronic duodenal ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.0",
          "display": "Acute peptic ulcer, site unspecified, with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.2",
          "display": "Acute peptic ulcer, site unspecified, with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.4",
          "display": "Chronic peptic ulcer, site unspecified, with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k27.6",
          "display": "Chronic peptic ulcer, site unspecified, with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.0",
          "display": "Acute gastrojejunel ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.2",
          "display": "Acute gastrojejunel ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.4",
          "display": "Chronic gastrojejunel ulcer with hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k28.6",
          "display": "Chronic Acute gastrojejunel ulcer with hemorrhage and perforation"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.01",
          "display": "Acute gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.31",
          "display": "Chronic gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.41",
          "display": "Chronic atrophic gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.51",
          "display": "Unspecified chronic gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.61",
          "display": "Other gastritis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.71",
          "display": "Gastritis, unspecified, with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.81",
          "display": "Duodenitis with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k29.91",
          "display": "Gastroduodenitis, unspecified, with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k31.811",
          "display": "Angiodysplasia –of stomach and duodenum with bleeding"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "k31.82",
          "display": "Dieulafoy lesion (hemorrhagic) of stomach and duodenum"
        }
      ]
    },
    {
      "id": "2b083e55-755c-432a-9d78-ac5f55787737",
      "display": "intracranial hemorrhage",
      "type": "NCIT_C113497",
      "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
      "members": [
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I62.0",
          "display": "Nontraumatic subdural hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I62.1",
          "display": "Nontraumatic extradural hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I62.9",
          "display": "Nontraumatic intracranial hemorrhage, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I69.2",
          "display": "Sequelae of other nontraumatic intracranial hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.0",
          "display": "Subdural hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.1",
          "display": "Cerebral hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.2",
          "display": "Intraventricular hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.3",
          "display": "Subarachnoid hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.4",
          "display": "Tentorial tear due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.8",
          "display": "Other intracranial lacerations and hemorrhages due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.9",
          "display": "Unspecified intracranial laceration and hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.0",
          "display": "Intraventricular (nontraumatic) hemorrhage, grade 1, of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.1",
          "display": "Intraventricular (nontraumatic) hemorrhage, grade 2, of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.2",
          "display": "Intraventricular (nontraumatic) hemorrhage, grade 3 and grade 4, of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.3",
          "display": "Unspecified intraventricular (nontraumatic) hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.4",
          "display": "Intracerebral (nontraumatic) hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.5",
          "display": "Subarachnoid (nontraumatic) hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.6",
          "display": "Cerebellar (nontraumatic) and posterior fossa hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.8",
          "display": "Other intracranial (nontraumatic) hemorrhages of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.9",
          "display": "Intracranial (nontraumatic) hemorrhage of newborn, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "S06.5",
          "display": "Traumatic subdural hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "S06.8",
          "display": "Other specified intracranial injuries"
        }
      ]
    },
    {
      "id": "5d5cf201-0a37-4c10-8397-da1aa774811e",
      "display": "cerebral hemorrhage",
      "type": "NCIT_C113497",
      "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
      "members": [
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.0",
          "display": "Nontraumatic intracerebral hemorrhage in hemisphere, subcortical"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.1",
          "display": "Nontraumatic intracerebral hemorrhage in hemisphere, cortical"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.2",
          "display": "Nontraumatic intracerebral hemorrhage in hemisphere, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.3",
          "display": "Nontraumatic intracerebral hemorrhage in brain stem"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.4",
          "display": "Nontraumatic intracerebral hemorrhage in cerebellum"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.5",
          "display": "Nontraumatic intracerebral hemorrhage, intraventricular"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.6",
          "display": "Nontraumatic intracerebral hemorrhage, multiple localized"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.8",
          "display": "Other nontraumatic intracerebral hemorrhage"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "I61.9",
          "display": "Nontraumatic intracerebral hemorrhage, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.0",
          "display": "Subdural hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.1",
          "display": "Cerebral hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.2",
          "display": "Intraventricular hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.3",
          "display": "Subarachnoid hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.4",
          "display": "Tentorial tear due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.8",
          "display": "Other intracranial lacerations and hemorrhages due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P10.9",
          "display": "Unspecified intracranial laceration and hemorrhage due to birth injury"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.0",
          "display": "Intraventricular (nontraumatic) hemorrhage, grade 1, of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.1",
          "display": "Intraventricular (nontraumatic) hemorrhage, grade 2, of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.2",
          "display": "Intraventricular (nontraumatic) hemorrhage, grade 3 and grade 4, of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.3",
          "display": "Unspecified intraventricular (nontraumatic) hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.4",
          "display": "Intracerebral (nontraumatic) hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.5",
          "display": "Subarachnoid (nontraumatic) hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.6",
          "display": "Cerebellar (nontraumatic) and posterior fossa hemorrhage of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.8",
          "display": "Other intracranial (nontraumatic) hemorrhages of newborn"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "P52.9",
          "display": "Intracranial (nontraumatic) hemorrhage of newborn, unspecified"
        },
        {
          "type": "IAO_0020000",
          "system": "http://www.nlm.nih.gov/research/umls/ICD-10-CM",
          "code": "S06.8",
          "display": "Other specified intracranial injuries"
        }
      ]
    },
    {
      "id": "484ef188-5765-408d-b8c3-f2f38ae8066c",
      "display": "topical or ophthalmic diclofenac",
      "type": "DIDEO_00000128",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1234735",
          "display": "diclofenac epolamine 0.0129 MG/MG Topical Gel"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "854801",
          "display": "Diclofenac Sodium Ophthalmic Solution"
        }
      ]
    },
    {
      "id": "818e9fed-e18d-45de-b900-1edbedee8c89",
      "display": "proton pump inhibitors",
      "type": "DIDEO_00000128",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "816346",
          "display": " Dexlansoprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "283742",
          "display": "  Esomeprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "17128",
          "display": " Lansoprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "7646",
          "display": " Omeprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "40790",
          "display": " Pantoprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "114979",
          "display": " Rabeprazole"
        }
      ]
    },
    {
      "id": "818e9fed-e18d-45de-b900-1edbedee8c89",
      "display": "misoprostols",
      "type": "DIDEO_00000128",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "42331",
          "display": " Misoprostol"
        }
      ]
    },
    {
      "id": "13d50375-4ad3-4d19-af8c-e13870b06907",
      "display": "corticosteroids",
      "type": "DIDEO_00000128",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1514",
          "display": "Betamethasone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "2878",
          "display": "Cortisone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "3264",
          "display": "Dexamethasone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "4452",
          "display": "Fludrocortisone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "5492",
          "display": "Hydrocortisone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "6902",
          "display": "Methylprednisolone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "8638",
          "display": "prednisolone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "8640",
          "display": "Prednisone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "10759",
          "display": "Triamcinolone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085795",
          "display": "100 ACTUAT Triamcinolone Acetonide 0.055 MG/ACTUAT Nasal Inhaler"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "833245",
          "display": "120 ACTUAT Triamcinolone Acetonide 0.05 MG/ACTUAT Nasal Inhaler"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085798",
          "display": "120 ACTUAT Triamcinolone Acetonide 0.055 MG/ACTUAT Nasal Inhaler"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1493473",
          "display": "60 ACTUAT Triamcinolone Acetonide 0.055 MG/ACTUAT Nasal Inhaler"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "670084",
          "display": "Betamethasone 0.12 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "308709",
          "display": "Betamethasone 0.6 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "578803",
          "display": "Betamethasone 3 MG/ML / Betamethasone acetate 3 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197543",
          "display": "Cortisone 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197545",
          "display": "Cortisone 5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "828248",
          "display": "cortisone acetate 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "309686",
          "display": "Dexamethasone 0.1 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197577",
          "display": "Dexamethasone 0.5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "854177",
          "display": "Dexamethasone 0.7 MG Drug Implant"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "343033",
          "display": "Dexamethasone 0.75 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197579",
          "display": "Dexamethasone 1 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "309684",
          "display": "Dexamethasone 1 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197580",
          "display": "Dexamethasone 1.5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "309696",
          "display": "Dexamethasone 10 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197581",
          "display": "Dexamethasone 2 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197582",
          "display": "Dexamethasone 4 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197583",
          "display": "Dexamethasone 6 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1116927",
          "display": "Dexamethasone phosphate 4 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "313979",
          "display": "Fludrocortisone 0.1 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "260192",
          "display": "Hydrocortisone 0.01 MG/MG Rectal Ointment"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310878",
          "display": "Hydrocortisone 1.67 MG/ML Enema"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197782",
          "display": "Hydrocortisone 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310868",
          "display": "Hydrocortisone 10 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1494032",
          "display": "Hydrocortisone 10 MG/ML Vaginal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310899",
          "display": "Hydrocortisone 2 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197783",
          "display": "Hydrocortisone 20 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1246528",
          "display": "Hydrocortisone 25 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "310879",
          "display": "Hydrocortisone 25 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199320",
          "display": "Hydrocortisone 4 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197787",
          "display": "Hydrocortisone 5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "238755",
          "display": "Hydrocortisone 50 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1012221",
          "display": "hydrocortisone acetate 0.0055 MG/MG / Lidocaine Hydrochloride 0.028 MG/MG Rectal Gel"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1012223",
          "display": "hydrocortisone acetate 0.025 MG/MG / Lidocaine Hydrochloride 0.03 MG/MG Rectal Gel"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1012229",
          "display": "hydrocortisone acetate 10 MG/ML / Lidocaine Hydrochloride 30 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1235049",
          "display": "hydrocortisone acetate 10 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "828362",
          "display": "hydrocortisone acetate 10 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Foam"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1545172",
          "display": "hydrocortisone acetate 100 MG/ML Rectal Foam"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1114854",
          "display": "hydrocortisone acetate 18.5 MG/ML / Pramoxine hydrochloride 11.5 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1012233",
          "display": "hydrocortisone acetate 20 MG/ML / Lidocaine Hydrochloride 20 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1094443",
          "display": "hydrocortisone acetate 23.5 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1291082",
          "display": "hydrocortisone acetate 25 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1294025",
          "display": "hydrocortisone acetate 25 MG/ML / Pramoxine hydrochloride 10 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1291085",
          "display": "hydrocortisone acetate 30 MG Rectal Suppository"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1012235",
          "display": "hydrocortisone acetate 5 MG/ML / Lidocaine Hydrochloride 30 MG/ML Rectal Cream"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199771",
          "display": "Methylprednisolone 100 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "328161",
          "display": "Methylprednisolone 16 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197969",
          "display": "Methylprednisolone 2 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197970",
          "display": "Methylprednisolone 24 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197971",
          "display": "Methylprednisolone 32 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "259966",
          "display": "Methylprednisolone 4 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "311659",
          "display": "Methylprednisolone 40 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "314099",
          "display": "Methylprednisolone 62.5 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1357886",
          "display": "Methylprednisolone 65.4 MG/ML Injectable Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "197973",
          "display": "Methylprednisolone 8 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1358510",
          "display": "methylprednisolone acetate 20 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1358610",
          "display": "methylprednisolone acetate 40 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1358617",
          "display": "methylprednisolone acetate 80 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199343",
          "display": "prednisolone 1 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "312614",
          "display": "prednisolone 1 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "643123",
          "display": "prednisolone 10 MG Disintegrating Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "643125",
          "display": "prednisolone 15 MG Disintegrating Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "794979",
          "display": "prednisolone 2 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "429199",
          "display": "prednisolone 20 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "199967",
          "display": "prednisolone 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "283077",
          "display": "prednisolone 3 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "793099",
          "display": "prednisolone 3 MG/ML Oral Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "643127",
          "display": "prednisolone 30 MG Disintegrating Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "702306",
          "display": "prednisolone 4 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198142",
          "display": "prednisolone 5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "249066",
          "display": "prednisolone 5 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1303125",
          "display": "Prednisone 1 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198144",
          "display": "Prednisone 1 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "315187",
          "display": "Prednisone 1 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198145",
          "display": "Prednisone 10 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1303132",
          "display": "Prednisone 2 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198146",
          "display": "Prednisone 2.5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "312615",
          "display": "Prednisone 20 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1303135",
          "display": "Prednisone 5 MG Delayed Release Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "312617",
          "display": "Prednisone 5 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "205301",
          "display": "Prednisone 5 MG/ML Oral Solution"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198148",
          "display": "Prednisone 50 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198301",
          "display": "Triamcinolone 1 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085728",
          "display": "Triamcinolone Acetonide 0.001 MG/MG Oral Paste"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085750",
          "display": "Triamcinolone Acetonide 10 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085754",
          "display": "Triamcinolone Acetonide 40 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085996",
          "display": "triamcinolone hexacetonide 20 MG/ML Injectable Suspension"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "1085992",
          "display": "triamcinolone hexacetonide 5 MG/ML Injectable Suspension"
        }
      ]
    },
    {
      "id": "a32b4ed0-1aff-4520-a973-879f705a0366",
      "display": "aldosterone antagonists and products containing an aldosterone receptor antagonist",
      "type": "DIDEO_00000128",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "298869",
          "display": "eplerenone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "9997",
          "display": "Spironolactone"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "351256",
          "display": "eplerenone 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "351257",
          "display": "eplerenone 50 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198224",
          "display": "Hydrochlorothiazide 25 MG / Spironolactone 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198225",
          "display": "Hydrochlorothiazide 50 MG / Spironolactone 50 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198222",
          "display": "Spironolactone 100 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "313096",
          "display": "Spironolactone 25 MG Oral Tablet"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "198223",
          "display": "Spironolactone 50 MG Oral Tablet"
        }
      ]
    }
  ]
}

A.5.2 Example 2: Tyrosine Kinase inhibitors and medications that increase gastric pH

Example 3: Tyrosine Kinase inhibitors and medications that increase gastric pH

{
  "drugs involved": [
    {
      "type": "DIDEO_00000128",
      "id": "48695d2d-9545-4a31-80d1-201d7d7e2cdb"
    },
    {
      "type": "DIDEO_00000128",
      "id": "05b06c16-a763-4ef4-90d8-899abb34abd8"
    }
  ],
  "clinical consequences": {
    "type": "MPIO_0000003",
    "id": "5476c5b5-b52b-4750-882d-cc47f4fa52f4",
    "display": "Decreased efficacy relative to treatment for chronic myeloid leukemia.",
    "concept set references": [
      {
        "type": "TextQuoteSelector",
        "exact": "chronic myeloid leukemia",
        "body": {
          "type": "SemanticTag",
          "value": "2e1bca79-953c-4ea3-9c40-4c16da2dde31"
        }
      }
    ]
  },
  "seriousness": {
    "type": "MPIO_0000009",
    "id": "d8ea3c5c-bc25-4cca-b9a8-ed742742e741",
    "value": "serious",
    "display": "A decrease in chronic myeloid leukemia treatment efficacy is a serious potential clinical consequence because it can result in death, life-threatening hospitalization, and disability."
  },
  "mechanism of interaction information": {
    "type": "MPIO_0000005",
    "id": "8a8ce6c0-c78e-4d38-bda2-835118f976ea",
    "display": "These TKIs demonstrate pH dependent absorption for oral administration which may result in decreased efficacy when given concomitantly with medications that increase gastric pH."
  },
  "frequency of exposure to the PDDI": {
    "type": "MPIO_0000007",
    "id": "56ebf54f-a148-4f2d-9924-b44f174ea72e",
    "display": "Unknown"
  },
  "frequency of harm for persons who have been exposed to the PDDI": {
    "type": "MPIO_0000006",
    "id": "207ae890-3098-436d-b248-578279c65d9c",
    "display": "Unknown"
  },
  "modifying factors information": {
    "type": "MPIO_0000000",
    "id": "b4566e23-3884-495f-93e1-04a0b5c9a008",
    "expressionLogic": "human readable",
    "members": [
      {
        "display": "The TKI is imatinib or ponatinib",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "No special precautions."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Imatinib and ponatinib AUCs are not appreciably decreased by PPI co-administration.",
          "References": [
            {
              "title": "Iclusig",
              "author": [
                {
                  "name": "ARIAD Pharmaceuticals, Inc."
                }
              ],
              "type": "package insert",
              "year": "2016",
              "link": [
                {
                  "url": "https://specialtydrug.magellanprovider.com/media/32235/iclusig.pdf"
                }
              ]
            },
            {
              "title": "Effect of a proton pump inhibitor on the pharmacokinetics of imatinib",
              "author": [
                {
                  "name": "Merrill J Egorin"
                },
                {
                  "name": "Dhvani D Shah"
                },
                {
                  "name": "Susan M Christner"
                },
                {
                  "name": "Mara A Yerk"
                },
                {
                  "name": "Kristin A Komazec"
                },
                {
                  "name": "Leonard R Appleman"
                },
                {
                  "name": "Robert L Redner"
                },
                {
                  "name": "Brian M  Miller"
                },
                {
                  "name": "Jan H Beumer"
                }
              ],
              "type": "article",
              "year": "2009",
              "journal": {
                "name": "British journal of clinical pharmacology",
                "volume": "68",
                "number": "3",
                "pages": "370--374"
              },
              "link": [
                {
                  "url": "https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2125.2009.03466.x"
                }
              ],
              "identifier": [
                {
                  "type": "doi",
                  "id": "10.1111/j.1365-2125.2009.03466.x"
                }
              ]
            }
          ]
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "Imatinib",
            "body": {
              "type": "SemanticTag",
              "value": "bd1da3d0-0543-42b6-9698-62f672d20ea4"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "ponatinib",
            "body": {
              "type": "SemanticTag",
              "value": "901791fd-5575-49fd-b043-a865743432b6"
            }
          }
        ]
      },
      {
        "display": "The TKI is nilotinib",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "Assess risk and take action if necessary."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Bosutinib and nilotinib AUCs are decreased with concomitant PPIs but antacids and H2 antagonists may be considered if TKI is given 2 hours before the antacid/H2 antagonist. However, for nilotinib a retrospective study has shown no difference in cytogenetic response rates for patients taking PPIs.",
          "References": [
            {
              "title": "Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia",
              "author": [
                {
                  "name": "Ophelia QP Yin"
                },
                {
                  "name": "Frank J Giles "
                },
                {
                  "name": "Michele Baccarani"
                },
                {
                  "name": "Philipp Le Coutre"
                },
                {
                  "name": "Ovidiu Chiparus"
                },
                {
                  "name": "Neil Gallagher"
                },
                {
                  "name": "Giuseppe Saglio"
                },
                {
                  "name": "Timothy P Hughes"
                },
                {
                  "name": "Andreas Hochhaus"
                },
                {
                  "name": "Hagop M Kantarjian"
                },
                {
                  "name": "RA Larson"
                }
              ],
              "type": "article",
              "year": "2012",
              "journal": {
                "name": "Cancer chemotherapy and pharmacology",
                "volume": "70",
                "number": "2",
                "pages": "345--350"
              },
              "link": [
                {
                  "url": "https://link.springer.com/article/10.1007/s00280-012-1881-3"
                }
              ],
              "identifier": [
                {
                  "type": "doi",
                  "id": "10.1007/s00280-012-1881-3"
                }
              ]
            }
          ]
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "nilotinib",
            "body": {
              "type": "SemanticTag",
              "value": "d8dc65de-aefc-45a1-a0b5-d576838bcb1b"
            }
          }
        ]
      },
      {
        "display": "The TKI is bosutinib or dasatinib",
        "type": "MPIO_0000111",
        "operational classification statement": {
          "type": "MPIO_0000111",
          "display": "Use only if benefit outweighs risk."
        },
        "evidence about a suspected drug-drug interaction": {
          "type": "MPIO_0000004",
          "display": "Bosutinib and nilotinib AUCs are decreased with concomitant PPIs but antacids and H2 antagonists may be considered if TKI is given 2 hours before the antacid/H2 antagonist.",
          "References": [
            {
              "title": "Sprycel",
              "author": [
                {
                  "name": "Bristol-Myers Squibb Company"
                }
              ],
              "type": "package insert",
              "year": "2015",
              "link": [
                {
                  "url": "https://packageinserts.bms.com/pi/pi_sprycel.pdf"
                }
              ]
            },
            {
              "title": "Bosulif",
              "author": [
                {
                  "name": "Pfizer Labs"
                }
              ],
              "type": "package insert",
              "year": "2015",
              "link": [
                {
                  "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203341lbl.pdf"
                }
              ]
            },
            {
              "title": "Tasigna",
              "author": [
                {
                  "name": "Novartis"
                }
              ],
              "type": "package insert",
              "year": "2015",
              "link": [
                {
                  "url": "https://www.accessdata.fda.gov/drugsatfda_docs/label/2007/022068lbl.pdf"
                }
              ]
            }
          ]
        },
        "concept set references": [
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "bosutinib",
            "body": {
              "type": "SemanticTag",
              "value": "3b4fd6a6-15a8-4520-8ec4-ffb62898bc33"
            }
          },
          {
            "type": "TextQuoteSelector",
            "attribute": "display",
            "exact": "dasatinib",
            "body": {
              "type": "SemanticTag",
              "value": "e57501f1-5af2-4479-99c6-dc971e1dec35"
            }
          }
        ]
      }
    ]
  },
  "concept sets": [
    {
      "id": "2e1bca79-953c-4ea3-9c40-4c16da2dde31",
      "display": "chronic myeloid leukemia",
      "type": "SNOMED-CT",
      "system": "https://www.nlm.nih.gov/healthit/snomedct/",
      "members": [
        {
          "type": "IAO_0020000",
          "system": "https://www.nlm.nih.gov/healthit/snomedct/",
          "code": "415287001",
          "display": "Relapsing chronic myeloid leukemia"
        },
        {
          "type": "IAO_0020000",
          "system": "https://www.nlm.nih.gov/healthit/snomedct/",
          "code": "277589003",
          "display": "Atypical chronic myeloid leukemia"
        },
        {
          "type": "IAO_0020000",
          "system": "https://www.nlm.nih.gov/healthit/snomedct/",
          "code": "277587001",
          "display": "Juvenile chronic myeloid leukemia"
        },
        {
          "type": "IAO_0020000",
          "system": "https://www.nlm.nih.gov/healthit/snomedct/",
          "code": "128826001",
          "display": "Atypical chronic myeloid leukemia, BCR/ABL negative"
        }
      ]
    },
    {
      "id": "48695d2d-9545-4a31-80d1-201d7d7e2cdb",
      "display": " tyrosine kinase inhibitors (TKIs)",
      "type": "DIDEO_00000128",
      "system": "https://www.whocc.no/atc_ddd_index",
      "members": [
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XE04",
          "display": "sunitinib"
        },
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XC03",
          "display": "trastuzumab"
        },
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XC14",
          "display": "ado-trastuzumab emtansine"
        }
      ]
    },
    {
      "id": "05b06c16-a763-4ef4-90d8-899abb34abd8",
      "display": "proton pump inhibitors",
      "type": "DIDEO_00000128",
      "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
      "members": [
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "816346",
          "display": " Dexlansoprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "283742",
          "display": "  Esomeprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "17128",
          "display": " Lansoprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "7646",
          "display": " Omeprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "40790",
          "display": " Pantoprazole"
        },
        {
          "type": "APOLLO_SV_00000461",
          "system": "http://www.nlm.nih.gov/research/umls/rxnorm",
          "code": "114979",
          "display": " Rabeprazole"
        }
      ]
    },
    {
      "id": "bd1da3d0-0543-42b6-9698-62f672d20ea4",
      "display": "Imatinib",
      "type": "DIDEO_00000128",
      "system": "https://www.whocc.no/atc_ddd_index",
      "members": [
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XE01",
          "display": "imatinib"
        }
      ]
    },
    {
      "id": "901791fd-5575-49fd-b043-a865743432b6",
      "display": "ponatinib",
      "type": "DIDEO_00000128",
      "system": "https://www.whocc.no/atc_ddd_index",
      "members": [
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XE08",
          "display": "ponatinib"
        }
      ]
    },
    {
      "id": "d8dc65de-aefc-45a1-a0b5-d576838bcb1b",
      "display": "nilotinib",
      "type": "DIDEO_00000128",
      "system": "https://www.whocc.no/atc_ddd_index",
      "members": [
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XE08",
          "display": "nilotinib"
        }
      ]
    },
    {
      "id": "3b4fd6a6-15a8-4520-8ec4-ffb62898bc33",
      "display": "bosutinib",
      "type": "DIDEO_00000128",
      "system": "https://www.whocc.no/atc_ddd_index",
      "members": [
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XE14",
          "display": "bosutinib"
        }
      ]
    },
    {
      "id": "e57501f1-5af2-4479-99c6-dc971e1dec35",
      "display": "dasatinib",
      "type": "DIDEO_00000128",
      "system": "https://www.whocc.no/atc_ddd_index",
      "members": [
        {
          "type": "ATC",
          "system": "https://www.whocc.no/atc_ddd_index",
          "code": "L01XE06",
          "display": "dasatinib"
        }
      ]
    }
  ]
}

A Minimum Representation of Potential Drug-Drug Interaction Knowledge and Evidence - Technical and User-centered Foundation

Final Community Group Report 17 May 2019

Abstract

Status of This Document

1. Introduction

1.1 Need, envisioned workflow, and high-level requirements

2. The Minimum Information Model

2.1 Definitions of Core Information Items

3. A summary of recommendations related to the minimum information model

4. Knowledge representation for the minimal information model

5. Examples of the use of the minimal information model

5.1 Applying the Minimal Information Model definitions to the PDDI between warfarin and non-steroidal anti-inflammatory drugs (NSAIDs)

5.2 Applying the Minimal Information Model definitions to the PDDI between BCR-ABL Tyrosine Kinase Inhibitors (TKI) + Proton Pump Inhibitors (PPI)

6. Background and use cases

6.1 The overarching use case for the minimum information model

6.2 End-users of the minimum information model

7. Discussion

7.1 Shareable PDDI Clinical Decision Support Using HL7 Standards

7.2 Enhancing the Drug-drug Interaction Section of Structured Product Labeling

7.3 Highlighting and Filling Gaps in Evidence Needed to Develop PDDI Decision Support

8. Conclusion

9. Acknowledgments

A. Appendices

A.1 Development Process

A.1.1 Decision Trees

A.1.1.1 Selecting PDDIs to implement using the minimum information model

A.1.1.2 Decision Trees Created for the Minimum Information Model Domain Analysis

A.1.1.2.1 Example PDDI:Warfarin + NSAIDs

A.1.1.2.2 Example PDDI: BCR-ABL Tyrosine Kinase Inhibitors (TKI) + Proton Pump Inhibitors (PPI)

A.2 User Stories

A.2.1 Workflow for arriving at stories and goals

A.2.2 User stories for the minimum information model

A.2.2.1 Color codes used in user stories

A.2.2.2 A set of user stories focused on medication reconciliation

A.2.2.2.1 Use Story 1: Hospital Pharmacist, Medication Reconciliation upon Admission

A.2.2.2.2 User Story 2: Hospital Pharmacist, Medication Reconciliation upon Discharge

A.2.2.2.3 User Story 3: Consultant Pharmacist, Medication Reconciliation upon Readmission

A.2.2.3 Treatment Planning, Physician

A.2.2.4 Evaluation of Management Options for Drug-Drug Interactions, Physician

A.2.2.5 Evaluation of Management Options for Drug-Drug Interactions, Pharmacist

A.2.2.6 Screening for Drug-Drug Interactions, Nurse

A.2.2.7 Synthesis for Dissemination, Drug Compendium Editor

A.2.2.8 Synthesis for Dissemination, Librarian

A.2.2.9 Synthesis for Dissemination, Clinical Decision Support Team - Systems Analyst & Content Specialist

A.2.2.10 Out of scope user stories

A.3 Definition of guidelines for knowledge representation

A.4 Value Sets to Support PDDI Examples

A.4.1 Some Background on Concept Identification and 'Value Sets'

A.4.2 aldosterone antagonists and products containing an aldosterone receptor antagonist (RxNorm)

A.4.3 bosutinib (ATC)

A.4.4 cerebral hemorrhage (ICD-10-CM)

A.4.5 chronic myeloid leukemia (SNOMED-CT)

A.4.6 dasatinib (ATC)

A.4.7 upper gastrointestinal bleeding or peptic ulcer (ICD-10-CM)

A.4.8 imatinib (ATC)

A.4.9 intracranial hemorrhage (ICD-10-CM)

A.4.10 misoprostol (RxNorm)

A.4.11 nilotinib (ATC)

A.4.12 Systemic non-steroidal anti-inflammatory drugs (NSAIDs) (RxNorm)

A.4.13 ponatinib (ATC)

A.4.14 proton pump inhibitor (ATC)

A.4.15 proton pump inhibitor (RxNorm)

A.4.16 systemic corticosteroids (RxNorm)

A.4.17 topical or opthalamic diclofenac (RxNorm)

A.4.18 tyrosine kinase inhibitors (TKIs) (ATC)

A.4.19 warfarin (RxNorm)

A.5 JSON Examples

A.5.1 Example 1: warfarin and systemic non-steroidal anti-inflammatory drugs (NSAIDs)

A.5.2 Example 2: Tyrosine Kinase inhibitors and medications that increase gastric pH

B. References

B.1 Normative references

B.2 Informative references