1. Standardize 4 Safety: Concentrating on Concentrations
Michael Ganio, Pharm.D., M.S., BCPS, FASHP
Director, Pharmacy Practice and Quality
ASHP

3. ASHP IV Summit 2008 Multi-stakeholder IV summit was held in 2008
Goal of preventing patient harm and death from IV medication errors
Three main barriers were identified at the summit:
Lack of standardization and good process design for IV medications
Lack of shared accountability for safety among members of different healthcare disciplines
High-volume, high-demand environments in which safety may be sacrificed for other priorities
Proceedings of a summit on preventing patient harm and death from i.v. medication errors. July 14-15, 2008, Rockville, Maryland. Am J Health-Syst Pharm. 2008; 65:

4. ASHP IV Summit 2008 Multi-stakeholder IV summit was held in 2008
Goal of preventing patient harm and death from IV medication errors
Three main barriers were identified at the summit:
Lack of standardization and good process design for IV medications
Lack of shared accountability for safety among members of different healthcare disciplines
High-volume, high-demand environments in which safety may be sacrificed for other priorities
Proceedings of a summit on preventing patient harm and death from i.v. medication errors. July 14-15, 2008, Rockville, Maryland. Am J Health-Syst Pharm. 2008; 65:

5. Statement of the Problem
Example of different concentrations across transitions in care
Ambulance Amiodarone 360 mg/200 mL (1.8 mg/mL) Local Emergency Department 300 mg/250 mL (1.2 mg/mL) Tertiary ICU – Central line 750 mg/250 mL (3 mg/mL)
360 mg/200mL = commercially available premix

6. Statement of the Problem
No national consensus for standard concentrations of IV medications (continuous, intermittent, etc.)
Patients are transferred between patient care areas
During transport
Between hospitals
Level of care within hospital
Discharge
Potential for error
Often vulnerable patient populations involved
Critically ill
Pediatric, neonate
Geriatric

7. Standardize 4 Safety
The first national, interprofessional effort to standardize medication concentrations to reduce errors and improve transitions of care
Creating, testing, publicizing, and supporting the adoption of these national standardized medication concentrations
Supported by a contract with FDA Safe Use Initiative
AAMI = association for the advancement of medical instrumentation
PPAG = Pediatric Pharmacy Advocacy Group
ISMP = institute for safe medication practices

8. Standardize 4 Safety – Scope
Adult Continuous Infusions
Pediatric Continuous Infusions
Oral liquid standardized doses
PCA / Epidural infusions
Intermittent intravenous medications
Oral Compounded Liquids

9. Standardize 4 Safety – Scope
Adult Continuous Infusions
Pediatric Continuous Infusions
Oral liquid standardized doses
PCA / Epidural infusions
Intermittent intravenous medications
Oral Compounded Liquids
Intravenous standards Oral standards

10. Standardize 4 Safety – Methods
Expert-panel formation
Physicians, nurses, pharmacists spanning specialties including critical care, anesthesia, ED/trauma, medication safety, information technology
Data analysis
Sources include regional efforts in Maine, Indiana, North Carolina, San Diego
Expert panel meetings

11. Standardize 4 Safety – Methods
Publication of draft standards
Open for public review and comment
Internal ASHP staff review
ISMP review
Publication of final standards
Disseminate standards and promote adoption

12. Standardize 4 Safety – Guiding Principles
Patient Clinical Needs
FDA-approved commercial products
Limit to one concentration when possible
Use more concentrated when possible
Operational considerations (cost/waste)

13. Intravenous Standards

14. Intravenous Standards
“Adult”: Patients 50kg or greater
“Pediatric”: Patients under 50kg
Exclusions
Chemotherapy
Extracorporeal infusions (e.g. ECMO, CRRT)
Non-treatment doses (heparin for line patency)
Final volumes
Diluents (dextrose, saline, other)

15. Adult (50kg or above) Continuous Infusions
Alteplase
Amiodarone
Argatroban
Bumetanide
Cisatracurium
Dexmedetomidine
Diltiazem
Dobutamine
Dopamine
Epinephrine
Esmolol
Fentanyl
Furosemide
Heparin
Hydromorphone
Insulin
Isoproterenol
Labetolol
Lidocaine
Lorazepam
Morphine
Midazolam
Milrinone
Nicardipine
Nitroglycerin
Nitroprusside
Norepinephrine
Phenylephrine
Propofol
Rocuronium
Vasopressin
Vecuronium

16. Adult (50kg or above) Continuous Infusions

17. Intravenous Standards
Pediatric continuous infusion standards
Draft comments posted; comments collected
Review for publication of final standards
PCA / Epidural standards
Expert panel work completed
Compiling information for publication of draft standards
Intermittent infusion standards
Expert panel work underway

18. Intravenous Standards – Challenges
Differences between the OR and other areas
Paralytics
Straight drug vs. diluted or pharmacy-compounding infusions
Stability data
“we’ve always done it this way”
Drug shortages
Package size and dose mismatches
Example: package is mg/mL and dose is mcg/min or mcg/kg/min
Higher concentrations needed because of higher doses.
More concentrated vs. larger bag
Fluid restriction
Dosing unit of drug do not match package – concentration units don’t match dosing units (mg/mL vs. dosed in mcg/mL/hr or minute)

19. Compounded Oral Liquids

20. Problem Statement No national standard concentrations
Hospital pharmacies and community pharmacies use different recipes
Availability of recipes and ingredients
Duration of therapy (limited doses inpatient, multi-dose bottles outpatient)
Ease of preparation
Reimbursement

21. Problem Statement
Medication errors occur through improper medication reconciliation
Caregivers usually know volume or by syringe markings, not total dose
Directions often in volume (1 teaspoonful; 5 mL)
Correct medication history by viewing bottle label or contacting pharmacy

22. Problem Statement
Nearly 75% of the drugs available in the US for adults have not been labeled for use in infants and children <12 years
Off label drug use results in:
Using drugs that have not been adequately tested
Using dosage forms that are not suitable for administration to infants and children
Using a portion of solid dosage form
Increased demand for extemporaneous liquid formulations

23. Oral compounds – Guiding Principles
Patient Clinical Needs
FDA-approved commercial products
Limit to one concentration when possible
Pharmaceutics: taste, palatability
Primary literature support
Reimbursement for products used

24. Oral compounds – Guiding Principles
Ease of compounding
Preference for dye‐free compounding ingredients when possible
simple ingredients
readily available
Preference for commonly used and accepted concentrations
doesn’t require pH testing or addition of multiple complex ingredients
Existing USP monograph
Ease of measurement
Avoid potential for tenfold dosing errors
Concentration can be used for the majority of doses and won’t result in doses less than 0.1mL
Cultural considerations related to ingredients
Safe for diabetics or ketogenic diets (sugar-free compounding ingredients when possible)

25. Oral Compounds – Methods
Same methods as intravenous projects
Extensive work for recipe review
Must be in peer-reviewed article to be considered
Considered abstracts on case-by-case basis
Stability longer than seven days for reasonable refill schedule
Studies considered – published in peer-reviewed journal – details of entire product and procedure incl. ingredients, conditions, storage container
Some older studies used glass bottles – extrapolated to plastic
Rifampin originally used liquid injection – extrapolated to capsules
Ursodiol originally used tablets – extrapolated to capsules
Hydralazine 4mg/mL – only stable for 48 hours – Cutis pharma role? Or teach someone to crush/manipulate or powder sachets

26. Oral compounds
Standardized list for oral compounded liquid medications
Using State of Michigan project as a starting point

27. Oral Compound Standards
Version 1.01 includes 29 drugs and has been completed
Formulations (recipes) will be made available once the rights are formalized by the FDA

28. Oral Compounded List Version 1.01
Amiodarone 5 mg/mL or 20 mg/mL
Atenolol 2 mg/mL
Baclofen 5 mg/mL
Bethanacol 5 mg/mL
Captopril 1 mg/mL*
Chloroquine 10 mg/mL*
Clonidine 20 mcg/mL
Flecainide 20 mg/mL
Flucytosine 50 mg/mL*
Hydralazine 4 mg/mL1*
Hydrochlorothiazide 5 mg/mL
Hydrocortisone 2 mg/mL2
Hydroxyurea 100 mg/mL
Labetalol 40 mg/mL
Lansoprazole 3 mg/mL
Metoprolol 10 mg/mL
Metronidazole 50 mg/mL
Morphine (NAS) 0.4 mg/mL
Nifedipine 4 mg/mL
Pyrazinamide 100 mg/mL*
Rifampin 25 mg/mL*
Sodium chloride 4 mEq/mL
Spironolactone 5 mg/mL3
Tacrolimus 1 mg/mL*
Thioguanine 20 mg/mL
Topiramate 20 mg/mL4
Ursodiol 60 mg/mL*
Valacyclovir 50 mg/mL
Zonisamide 10 mg/mL
Oral liquids for anyone who cannot take solid dosage form (pediatrics, geriatric patients, feeding tubes, etc.)
S4S fully recognizes the mismatch between USP monograph concentration differences.
Went with USP monograph when possible but ultimately determined concentration based on data on what was being used in practice (80/20 rule).
Bold – USP monograph exists
* - USP monograph strength different than S4S

29. Oral Compounds – Challenges
Data!!
Formulations (i.e. recipes)
Some internal
Literature review was intense and took much longer than anticipated
Some information in abstract only
Rights to information
For example: topiramate (owned by USP)
Competing with large compounding groups
Again reference to literature criteria
Some of the monographs are internal use
Most compounders aren’t using nifedipine powder, so S4S is using 4mg/mL from capsules is more common than a 5mg/mL recipe that is from bulk API powder

30. Oral Compounds – Challenges
Ingredient availability
Common ingredients vs. complex formulations
Powders vs. solid dosage forms
Larger compounding facilities use API powders
(e.g. nifedipine powder)

31. Oral liquid standardized doses
Weight-based doses
Can result in difficult-to-measure volumes
Therapeutic window
Rounding vs. standardizing
EHR abilities/limitations
Accurate measurement and measurement literacy
Expert committee work underway

32. What You Can Do Start planning Be a champion, cheerleader, sponsor
Don’t just get buy-in, take ownership
Remember to take an interprofessional approach
Including informatics team!
Resources: REMEDI, ISMP IPI, Bainbridge Health, ASHP, eBroselow, new potential tools in the pipeline

33. Questions?