GXP

Medication Safety – Pharma Industry Considerations Questions From Readers #2

INTRODUCTION

The Journal of GXP Compliance (JGXP) initiated a series of discussions on medication safety topics several months ago.  These discussions were intended to introduce pharma industry personnel to the problems and experiences of healthcare practitioners with actual use of pharma products. Several questions and clarifications about topics in these discussions have recently been requested.

Pharma personnel know primarily about the products made by their respective companies. They are knowledgeable of product design and development approaches, clinical testing, and regulatory compliance within their companies.  Specific activities include formulation, manufacturing processes, packaging, labeling, formats, coloration, documentation, graphics, and many others comprising a broad scope of knowledge. Introducing medication safety considerations to pharma industry personnel with these responsibilities should help integrate potential safety issues into industry practices to minimize potential medication problems – a positive outcome for healthcare practitioners, for patients, and for pharma industry.

JGXP Medication Safety Papers

The initial paper (1) in this series provided a general overview of medication safety considerations and identified topics for subsequent discussion; the many causes for medication errors was discussed. The following paper (2) focused on medication problems associated with drug names.  Supportive to this paper were individual papers describing basics of small molecule drug and biologic drug names.  Small molecule drug names (3) discussed chemical, non-proprietary (generic) and proprietary names. Biologic drug names (4) discussed biosimilar and proprietary product names. Formats, prefixes, infixes, suffixes, regulatory requirements, FDA Orange Book, FDA Purple Book, and associated name information were addressed.  Also presented were a Q&A paper (5) and podcast (6) further clarifying naming complexities. The next paper (7) introduced high-alert medications, a specific subset of drugs that have significant consequences including fatalities for patients if medication errors occur. Several of the above suggested specific considerations for industry related to medication safety.

Reader Questions

Content addressed in the present discussion responds to new comments and questions about recently introduced medication safety topics. It builds on previous questions (5,6) that addressed basics of drug naming, small molecules and biologic drug name stems, biologic drug name schemes, comparing generics and biosimilars, FDA name requirements for biosimilars, and miscellaneous confusing naming terminology.

The following new questions are addressed:

  • Medication process.  What is the medication process?
  • Narrow therapeutic index drugs.  What is a therapeutic index?
  • Opioid narcotic activity.  What are differences in activities of opioids?
  • Antithrombotic / anticoagulant therapy.  What are problems with antithrombotic therapy?
  • Dosage calculations.  What are some examples of problem calculations?

TOPIC #1.  WHAT IS THE MEDICATION PROCESS?

Several examples of medication errors in the high-alert medication discussion (7) referred to the “medication process.” This term comprehensively describes the actual handling and use of medications by healthcare practitioners after product is commercially available.  Activity categories in medication process listings are thorough and inclusive; they identify many less obvious activities that may contribute to medication errors. For example, the medication process recognizes storage of drugs in various hospital departments and satellite locations, access to drug products with high risk of misuse, and healthcare setting working conditions that may contribute medication errors.  Consideration of the comprehensive medication process as listed below serves to increase awareness of the potential for medication errors in both obvious and less visible activities in the healthcare setting.

ISMP Key Elements of Medication Use System™ (8)

The Institute for Safe Medication Practice has developed a listing of key elements of the medication process.  This listing provides framework for evaluating potential medication safety situations in healthcare settings and various treatment applications.  It identifies ten general categories of activities; see Table below.  Each of these have individual considerations depending on the healthcare setting; for example, ISMP has published a comprehensive handbook for community pharmacy practice (9) and a medication safety self-assessment for antithrombic therapy (10).

TABLE 1.  ISMP KEY ELEMENTS OF MEDICATION USE (X)

#

ELEMENT

DESCRIPTION

1

Patient information

Obtain patient demographic and clinical information relevant to drug therapy to prevent adverse drug events (ADE)

2

Drug information

Provide current drug information on relevant drugs

3

Communication of drug information

Facilitate drug information communication between healthcare practitioners (physicians à pharmacists à nurses à others)

4

Drug labeling, packaging, and nomenclature

Drug names that look alike/sound alike (LASA), similar labeling and packaging, and related considerations contribute to medication errors

5

Drug storage, stock, standardization, and distribution

Standardized drug products, concentrations, administration times, and limiting dosages with minimize ADE

6

Drug device acquisition, use, and monitoring

Safety of drug delivery devices must be assessed.  Double checks of drug selection, drug concentration, administration rates, and infusion lines should be implemented

7

Environmental factors

Working conditions including lighting, noise, interruptions, and excessive workloads

8

Staff competency and education

Staff education must be prioritized to focus on highest priority medication safety topics such as new drugs, high-alert drugs, internal and external medication errors, and related considerations

9

Patient education

Patients must receive ongoing education from physicians, pharmacists, nurses, and others about the drugs they are receiving regarding, indications, doses, adverse effects, incompatibilities, and other relevant information

10

Quality processes and risk management

Systems and processes must be redesigned to prevent the potential for medication errors rather than responding to actual incidences of error

ASHP Guidelines on Preventing Medication Errors in Hospitals (11)

The American Society of Health System Pharmacists (ASHP) has published a comparable listing of elements in a medication use system primarily directed to hospital practice settings; see Figure 2.  This listing expands a previous listing by The Joint Commission and includes patient admission and patient discharge as discrete activities.  Each of the identified activities are discussed including specific applications.  The value of the ASHP and ISMP documents is to heighten awareness of potential medication safety risks in less obvious areas of healthcare practice.

TABLE 2.  ASHP MEDICATION USE SYSTEM (11)

#

ELEMENT

DESCRIPTION

CONTENT

1

Planning

Organizational priority and comprehensive system

Patient safety culture

Error reporting and review

Root cause analysis

Risk assessment

Error risk reduction

High-alert medications

Safety strategies

Independent double-checks

Risk evaluation and mitigation strategy (REMS)

2

Selection and procurement

Product selection for addition to hospital formulary

Supply chain considerations

Formulary assessment and management

Standard concentrations

Safety alert monitoring

Safe procurement

Medication shortage management.

3

Storage

Arrangement and storage of medication throughout facility

Steps to minimize wrong product selection

Inventory management and control

Storage restricted to pharmacy

Automated Dispensing Cabinets (ADC)

4

Patient admission

Patient admission process

Patient medication history

Medication reconciliation

5

Ordering, transcribing, and reviewing

Elements of the prescribing process in hospital system

Practitioner medication orders

Ordering errors and causative factors

Listing of specific errors

Electronic ordering systems and required inputs

6

Preparation

Pharmacy and other area preparation of commercial product

Description of errors

Facility and personnel requirements

Outside pharmacy medication preparation

Feeding tubes administration

Non-sterile preparations

Automated systems

USP guidelines

Neonates, infants, and pediatric preps

Oral syringes

7

Dispensing

Medication dispensing requirements

Pharmacist checking

Automated dispensing systems

Non-24/7 facilities

8

Administration

Drug administration errors

Five rights of medication administration

Enteral and IV tubing misconnection

Barcode systems

Smart infusion pumps

Practitioner education

Patient education

9

Monitoring

Monitoring considerations including drug erects, laboratory data, monitoring timing, data monitoring timing

Failure to monitor drug efficacy / toxicity

Incorrect interpretation of monitoring data

Incorrect transcription of test data

Incorrect timing – blood draws and other monitoring

10

Patient discharge

Discharge activities reduce ADE

Medication counseling of patients

Medication reconciliation

Patient role in preventing medication problems

11

Evaluation

Organization evaluation of systems

Self-assessments and FMEA

Root cause analysis – ADE and close-calls

Medication-use analysis

Quality improvement

Event detection-current organization performance and prevent future errors

TOPIC #2.  WHAT IS THE DRUG THERAPEUTIC INDEX?

Several of drugs identified as high-alert medications were also described as narrow therapeutic index drugs (NTI).  The therapeutic index of a drug is the ratio of the drug lethal dose to its therapeutic dose.

The therapeutic index is often expressed as the following equation:

The therapeutic index thus characterizes the safety or toxicity of a drug.  Consider the following with two examples Drug A and Drug B.

Drug A has a lethal dose of 20 mg and a therapeutic dose of 10 mg, its TI is 20/10 = 2.

Drug B had a lethal dose to 500 mg and a therapeutic dose of 10 mg, its TI is 500/10 = 50.

The smaller the TI, the more toxic is the drug.  In the above example, Drug A (TI = 2) is much more toxic than Drug B (TI = 50).  Drugs with very low TI around 2 or 3 and lower are termed narrow therapeutic index or NTI drugs.

Example NTI Drugs

Lists of NTI drugs are available from multiple references.  Examples of common NTI drugs include carbamazepine, cyclosporin digoxin, ethosuximide, levothyroxine, lithium, phenytoin, theophylline, and warfarin (12,13).

Related Terminology

Therapeutic Drug Monitoring.  A safe drug has a high TI – a very large toxic dose and a very small effective dose.  A dangerous drug has a low TI.  Patient therapy with a low TI drug may require therapeutic drug monitoring.  Therapeutic drug monitoring describes measurement of drug blood levels in patients to ensure dosage is safe and effective but not toxic – and within the drug therapeutic window.

Therapeutic Window.  The therapeutic window is the range of drug concentrations within which drug therapy is effective but not toxic.  If a low dosage of drug is effective and a high drug dosage is toxic, the therapeutic window is wide and drug therapy is safe.

Toxic Dose 50% or TD50.  Sometimes the lethal dose LD50 is described as the Toxic Dose or TD50

Effective Dose 50% or ED50.  Sometimes the therapeutic dose TD50 is described as the Effective Dose or ED50.

TOPIC #3.  WHAT ARE DIFFERENCES IN THE NARCOTIC ACTIVITIES OF OPIOIDS?

The topic of opioid narcotic activity was described in the high-alert medication discussion (7).  An example in which morphine and hydromorphone dosage confusion caused patient death was described; a patient with a chest injury was prescribed 10 mg IM morphine for pain but was erroneously administered 10 mg. hydromorphone.  The hydromorphone dose was equivalent to 60-70 mg morphine – a significant overdose of hydromorphone causing: the patient death.

Table 3 describes the relative potency of various opioid narcotic drugs; this equivalency is termed “equianalgesic dosing.”  Drug dosage of other opioid drugs is usually compared to a standard dose of morphine.  Common proprietary names of certain products are listed parenthetically. 

TABLE 3.  OPIOID EQUIANALGESIC DOSING

DRUG

PARENTERAL DOSE (MG)

ORAL DOSE (MG)

Morphine

10

30

Codeine

100

200

Fentanyl (Duragesic®)

0.1

NA

Hydrocodone

NA

30

Hydromorphone (Dilaudid®)

1.5

7.5

Meperidine (Demerol®)

100

300

Oxycodone (Oxycontin®)

10

20

Oxymorphone

1

10

Many of the above are available in combination products.  Some of the more common products include acetaminophen and codeine (Tylenol with Codeine® [multiple strengths]), acetaminophen and hydrocodone (Norco®, Vicodin®), acetaminophen and oxycodone (Percocet®), aspirin and oxycodone (Percodan®), and many others. (14-16)

Note the following from Table 3:

  • Name similarities:  Morphine, hydromorphone, and oxymorphone; codeine, hydrocodone, and oxycodone.  Name confusion is a cause of errors
  • Oral hydromorphone is 4x more potent than oral morphine; 7.5 mg oral hydromorphone = 30 mg oral morphine
  • Parenteral hydromorphone is 7x more potent than parenteral morphine; 1.5 mg IV hydromorphone = 10 mg IV morphine
  • Parenteral hydromorphone is 20x more potent than oral morphine; 1.5 mg IV hydromorphone = 30 mg oral morphine
  • Fentanyl is significantly more potent than other opioids.  Fentanyl dosage is in micrograms; other opioids are dosed in milligrams.

Drug changes, conversions from IV to oral, and simple name confusion (morphine, meperidine, hydromorphone, codeine, hydrocodone, and so on) all contribute to opioid medication errors.  For example, a patient may be receiving IV morphine when hospitalized.  After discharge, continued narcotic treatment using oral tablets is desired.  Patient treatment must then be converted to an oral opioid with different equivalent therapeutic activity.  Confusion between morphine and hydromorphone is a longstanding medication error of this type.

TOPIC #4.  WHAT ARE PROBLEMS WITH ANTITHROMBOTIC/ANTICOAGULANT THERAPY?

Antithrombotic / anticoagulant therapy describes treatment for various circulatory and cardiac conditions such as atrial fibrillation (AFib), peripheral artery disease (PAD), venous thromboembolism (VTE), ad related conditions.  Drugs used in this therapy prevent blood clot (thrombus) formation and clot size increase.  Patients with AFib may have clots that travel to the brain causing a stroke.  Drugs involved in this therapy are commonly known as “blood thinners” although they function according to identified physiologic biochemical processes.

Antithrombotic / anticoagulant activities has been identified as a source of medication safety problems for many years.  Original drugs used in this therapy are heparin injection and warfarin (Coumadin®) tablets.  More recent therapy with direct oral anticoagulant (DOAC) products such as dabigatran (Pradaxa®), apixaban (Eliquis®), and rivaroxaban (Xarelto®) have lessened but not eliminated medication error risks.

Major Risk:  Bleeding

Excessive bleeding is the primary risk for patients being treated with antithrombotic drugs.  Patients on warfarin are periodically monitored by an INR (International Normalized Ratio) blood test; warfarin dosage may be modified depending on test results.  Warfarin treatment may be affected by other drugs, nutritional supplements, certain foods (Figure 1), as well as individual patient variation.  Patients taking DOAC drugs do not require blood monitoring and have fewer food and drug interactions.  Patients taking any antithrombotic drug should be wary of signs indicating unusual bleeding such as blood in urine or feces, bruising, dizziness, or headache.  DOAC drugs have been reported to cause fewer bleeding incidents than heparin or warfarin, and most bleeding incidents have occurred with senior patients (60+ age) (17).

 Warfarin food reactions

FIGURE 1.  FOODS INTERACTING WITH WARFARIN 

Products and Dosage Strengths

Antithrombotic products are available in multiple dosage strengths and have multiple dosage regimens.

Warfarin is available in 9 dosage strengths (Figure 2).

Warfarin Products

FIGURE 2.  WARFARIN PRODUCTS

Dabigatran (Pradaxa) is available as 75 mg and 150 mg capsules.

Apixaban (Eliquis®) is available as 2.5 mg and 5 mg tablets.

Rivaroxaban (Xarelto) is available as 2.5 mg, 10 mg, 15 mg, and 20 mg tablets, and as powder for oral suspension 1 mg / mL.

Heparin is available in 1,000 u/mL, 5,000 u/mL, 10,000 u/mL, and 20,000 units / mL dosage strengths in various vials sizes (Figure 3).  Heparin is also available in 10 u/mL and 100 u/mL for use in IV line patency.  See below for comments on heparin calculations.

Heparin Products

FIGURE 3.  REPRESENTATIVE HEPARIN PRODUCTS

 

ISMP High-Alert Medication Learning Guides (18)

ISMP has issued High-Alert Medication Learning Guides for warfarin, apixaban, dabigatran, enoxaparin, and rivaroxaban.  These guides emphasize medication safety risks when taking these drugs.  They specify information that should be communicated to health practitioners, signs of bleeding, i.e., drug dosage is too high; signs of a clot or stroke, i.e., drug dosage is too low; and signs of drug allergy.

ISMP Medication Safety Self-Assessment® for Antithrombotic Therapy

ISMP issued a comprehensive self-assessment for healthcare settings with antithrombotic therapy patients utilizing the ISMP Medication Use System (10) described above.  This document provides a checklist against core characteristics for each element in the medication process.  More than 100 checklist items are identified for evaluation against eleven antithrombotic therapy core characteristics; see Table 3.  This compilation demonstrates numerous opportunities and contributing factors for medication errors with antithrombotic drug products.

TABLE 3.  ISMP MEDICATION SAFETY SELF-ASSESSMENT FOR ANTITHROMBOTIC THERAPY (10)

 

ELEMENT

CORE CHARACTERISTIC

CHECKLIST ITEM

1

Patient Information

1.Essential patient information is obtained and readily available in a useful form when prescribing, dispensing, administering, and monitoring antithrombic therapy.

2. Essential patient information is used to monitor and manage the effects of antithrombotic therapy, and to adjust the treatment plan when indicated by evidenced-based practices.

1 – 18
 
 
 
 
19 - 26-

2

Drug Information

3. Essential drug information is obtained and readily available in a useful form when prescribing, dispensing, administering, and monitoring antithrombic therapy. 

4. Essential drug information is readily available in a useful form to guide the management of adverse drug reactions that may occur when antithrombotic agents are prescribed.

27 – 39
 
 
 
 
40 - 51

3

Communication of Drug Orders and Other Drug Information

5. Methods of communicating orders for antithrombotic drugs and other essential drug information are standardized and automated to minimize the risk for error.

52 - 60

4

Drug Storage, Stock, Standardization, and Distribution

6. Antithrombotic concentrations, doses, and administration times are standardized whenever possible.

61 - 71

5

Medication Device Acquisition, Use, and Monitoring

7. The potential for human error is mitigated through careful procurement, maintenance, use, and standardization of devices used to deliver medications and provide test results.

72 - 76

6

Competency and Staff Education

8. PRACTITIONERS receive sufficient orientation to organizational protocols and policies for antithrombotic therapy and undergo a baseline and ongoing competency evaluation of knowledge and skills of related safe medication practices.

77 - 83

7

Patient Education

9. Patients are included as active participants in their antithrombic therapy through education about their medications and ways to avert errors.  There is a transition of care process as part of discharge planning and education.

84 - 107

8

Quality Processes and Risk Management

10. PRACTITIONERS are stimulated to detect and report errors, and interdisciplinary teams regularly analyze errors that have occurred within the organization and in other organizations for the purpose of redesigning systems to best support safe PRACTITIONER performance.

11. Simple redundances that support a system of INDEPENDENT DOUBLE CHECKS are used for vulnerable parts of antithrombotic therapy to detect and correct serious errors before they reach patients.

108 – 112

 

  

 

113 - 115

TOPIC #5.  WHAT ARE SOME PROBLEM CALCULATIONS?

Dosage calculations are a well-known source of medication errors.  Drug administration often comprises a sequence of calculations beginning with the dosage order from the physician expressed as drug dose per patient weight.  Drug amount is ultimately calculated, usually in mL of a commercial product with a mg/mL concentration.  Multiple calculations are required to determine the product amount for administered to the patient.

Complicating this basic calculation is the range of patient weights – neonatal, pediatric, adolescent, adult, and senior; each of these age groups may have different dosages and other physiologic considerations.  Patient weights are usually available in kilograms (kg), although sometimes only pounds (lbs) are available.  Dosages in pediatrics or small children are sometimes ordered per body surface area calculated using the child’s weight and height.

Multiple dosage forms containing the same drug with different dosage strengths may be available.  For example, an injection product may be available in mg/mL often with multiple dosage strength; an oral children’s product is available in a different concentration mg/mL, and an adult tablet product is available in multiple dosage strengths containing mg/tablet.

Other Drug Product Units of Measure

Drug calculations may have variations such as with drugs that are dosed in units such as for insulin, heparin, and some antibiotics.  Electrolyte products such as potassium chloride are available in milliequivalents (mEq) per mL.  Phosphate injection is dosed in millimoles (mmoles).

Epinephrine/adrenaline products may be expressed in mg/ml or in ratio strength such as 1:1000, 1:10,000, and other ratios.  These expressions are defined in “parts,” i.e., 1 part in 1000 parts; parts may be grams, milligrams, mL, and other units.  USP has converted ration strength of epinephrine USP products to mg/mL notation; however, this change is not utilized globally.

Patient mg/kg Dosage and Product mL Dosage

The following demonstrates a typical calculation and equations to be executed beginning with the physician medication order and finishing with the drug amount to be administered.

 Fig 4

Product A is available as 50 mg / mL sterile solution in a 10 mL vial

  1. Patient weighs 154 lb.  Calculate patient weight in kg.
    154 lb  x  1 kg / 2.2 lb = 70 kg.

  2. Drug dosage is 2 mg / kg.  Calculate amount of drug to be administered.
    70 kg  x  2 mg / kg = 140 mg.

  3. Drug product available as 50 mg / mL solution.  Calculate amount of drug product needed.
    140 mg drug needed  x  ml / 50 mg = 2.8 mL needed.
     
  4. Drug is administered IV push at 50 mg / minute.  Calculate rate of administration.
    140 mg  x  minute / 50 mg = 2.8 minutes or ~ 3 minutes
    Administer 2.8 mL drug at approximately 1 mL / minute or 0.5 mL every 30 seconds.

Other Calculation Problems

Aside from correctly executing the above sequence of calculations, calculation errors may occur with leading zeros, training zeros, decimal point errors, microgram and milligram confusion, number transpositions, exponent errors, written number confusion, and combinations thereof.

ACKNOWLEDGMENTS

Helpful comments from Brad Bartels, PharmD, are gratefully acknowledged.

REFERENCES

  1. Mancini, Alan M.  Medication Safety – Pharma Industry Considerations.  Part 1, Problem Overview.  Journal GXP Compliance (JGXP), Volume 23, #3, May 2019. 
    https://www.ivtnetwork.com/article/medication-safety-industry-considerations-part-1-problem-overviewAccessed 2-21-22.
  2. Pluta, Paul L. Jenna Crosby, Michaela Murphy, Alan M. Mancini.  Regulatory 101:  Drug Names – Categories, Approval Processes, and Problems in Use.  JGXP, V23, #6, November 2019.  https://www.ivtnetwork.com/article/drug-names-%E2%80%93-categories-approval-processes-and-problems-use.  Accessed 2-22-22.
  3. Pluta, Paul L., Jenna Crosby, Michaela Murphy, and Alan M. Mancini.  Medication Safety – Pharma Industry Considerations Part 2 – Drug Names.  JGXP, Volume 23, #6, Nov 2019.  https://www.ivtnetwork.com/article/regulatory-101-medication-safety-industry-considerations-part-2-drug-names.  Accessed 1-20-22.
  4. Cieslak, Karolina, and Paul L. Pluta.  Regulatory 101:  Biologic Non-Proprietary Drug Names – Terminology and Format.  JGXP, V25, #2, March 2021.  https://www.ivtnetwork.com/sites/default/files/BIOLOGIC%20NON-PROPRIETARY%20DRUG%20NAMES%20%E2%80%93%20TERMINOLOGY%20AND%20FORMAT.pdf.  Accessed 2-22-22.
  5. Pluta, Paul L.  Regulatory 101.  Drug Names Reader Q&A.  JGXP, V25, #3, May 2021. https://www.ivtnetwork.com/article/regulatory-101-drug-names-%E2%80%93-reader-qa.  Accessed 2-22-22.
  6. Pluta, Paul L. and Karen R. Zimm.  Drug Naming and Medication Errors.  Voices in Validation Podcast, 6-8-21.  https://www.Drug Naming and Medication Errors | IVT (ivtnetwork.com), accessed 3-27-22.
  7. Reif, Brandon T., David J. An, Varanya Chaiyaperm, and Paul L. Pluta.  Medication Safety – Pharma Industry Considerations.  Part 3, High Alert Medications.  JGXP, Volume 26, #1, January 2022.  https://www.ivtnetwork.com/article/medication-safety-%E2%80%93-pharma-industry-considerations-part-3-%E2%80%93-high-alert-medications.  Accessed 2-22-22.
  8. ISMP.  Key Elements of Medication Use.  Key Elements of Medication Use | Institute for Safe Medication Practices (ismp.org).  Accessed 3-27-22.
  9. ISMP.  Medication Safety Self-Assessment for Community/Ambulatory Pharmacy.  1-23-2017.  Medication Safety Self-Assessment® for Community/Ambulatory Pharmacy | Institute for Safe Medication Practices (ismp.org).    Accessed 3-27-22.
  10. ISMP.  2017 Medication Safety Self-Assessment for Antithrombotic Therapy.  2017 ISMP Medication Safety Self-Assessment® for Antithrombotic Therapy.  Accessed 3-27-22.
  11. ASHP.  Guidelines on Preventing Medication Errors in Hospitals.  10-1-2018.  Preventing Medication Errors in Hospitals (ashp.org).  Accessed 3-27-22.
  12. Staiger, Brian.  What is Therapeutic Index and Why is it Important for Drugs?  www.walrus.com, 11-20-17.  What Is Therapeutic Index and Why Is It Important For Drugs (walrus.com).  Accessed 3-27-22.
  13. Smith, Robert.  Therapeutic Index.  Medbullets, 6-8-2021  Therapeutic Index - Pharmacology - Medbullets Step 1.  Accessed 3-27-22.
  14. World Health Organization.  Annex 6.  Pharmacologic Profiles and Opioid Conversion Tables. 2018.  Pharmacological Profiles and Opioid Conversion Tables - WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents - NCBI Bookshelf (nih.gov)  Accessed 3-27-22.
  15. Multicultural Palliative Care Equivalency Table.  Stanford Medicine.  Equivalency Table (stanford.edu), Accessed 3-27-22
  16. Analgesics, Opioid.  Medical Dictionary.  Gale Encyclopedia of Medicine, 2008.  Opioid analgesics | definition of opioid analgesics by medical dictionary (thefreedictionary.com),  Accessed 3-27-22.
  17. Valentine, David, Michael J. Gaunt, Matthew Grissinger.  Identifying Patient Harm from Direct Oral Anticoagulants.  Pennsylvania Patient Safety Authority, 6-15-2018.  Identifying Patient Harm from Direct Oral Anticoagulants | Advisory.  Accessed 3-27-22,
  18. ISMP.  High Alert Medication Learning Guides for Consumers.  11-2-18.  High-Alert Medication Learning Guides for Consumers | Institute for Safe Medication Practices (ismp.org).  Accessed 3-27-22.



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