508822

research-article2013

TDEXXX10.1177/0145721713508822Cochran et alUse of U-500R Insulin

Use of U-500R Insulin

153

Practice Tips and Tools for the

Successful Use of U-500
Regular Human Insulin
The Diabetes Educator Is Key

Abstract

Elaine K. Cochran, CRNP, BC-ADM

Virginia Valentine, CNS, BC-ADM, CDE, FAADE

ive-fold concentrated U-500 regular insulin

(500 units/mL) was introduced to the US market in 1952 (Iletin beef U-500; Eli Lilly and
Company, Indianapolis, Indiana) for use in
patients with extreme insulin resistance caused
by antibodies against animal-derived insulins1 and later
was used mainly for patients with syndromic/extreme
forms of insulin resistance (Iletin II pork U-500; Eli Lilly

Karen H. Samaan, PharmD, BCNSP

Ilene B. Corey, RN, PNP
Jeffrey A. Jackson, MD, CDE
From the National Institutes of Health/National Institute of Diabetes,
Digestive and Kidney Diseases, Bethesda, Maryland (Ms Cochran),
Diabetes Network, Inc, Albuquerque, New Mexico (Ms Valentine), St
Vincents Hospital, Indianapolis, Indiana (Dr Samaan), and Lilly USA, LLC,
Indianapolis, Indiana (Ms Corey, Dr Jackson).
Correspondence to Elaine Cochran, CRNP, BC-ADM, Digestive and Kidney
Diseases, National Institutes of Health/National Institute of Diabetes, 9000
Rockville Pike, 10/CRC 6-5940, Bethesda, MD 20892 (elainec@intra
.niddk.nih.gov).
Ms Cochran and Dr Samaan have no conflicts of interest to report. Ms
Valentine serves on advisory boards and speakers bureaus for Eli Lilly
and Company and for Amylin and on advisory boards for Novo Nordisk and
Halozyme. Ms Corey and Dr Jackson are full-time employees and minor
stockholders of Eli Lilly and Company.
Acknowledgments: A very special thanks to Jennie G. Jacobson, PhD, of
Eli Lilly and Company for her concise editing and logistical work to prepare
the manuscript for publication. We also thank Eileen Eisenhour for her
graphic art assistance.
DOI: 10.1177/0145721713508822
2013 The Author(s)

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tool
chest

This review provides information to equip diabetes educators to instruct and guide patients in using U-500
human regular insulin (U-500R). The article includes an
overview of U-500R pharmacology and clinical data,
strategies for outpatient and inpatient use, and tools for
patient education. U-500R is useful for treating patients
with any type of diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high doses of U-100 insulin, making treatment
with high doses of insulin more feasible (because of the
need for fewer injections for patients) as well as more
cost-efficient and potentially more effective. These tools
can help diabetes educators feel more comfortable and
confident as they advise and educate patients who
receive high-dose U-500R as part of their overall diabetes care plan. The diabetes educator plays a vital role in
helping patients use U-500R safely and successfully.

The Diabetes EDUCATOR

154

and Company, 1980).2 The only formulation available

today, U-500 regular human insulin (U-500R; Humulin
R U-500; Eli Lilly and Company, 1997), is growing in use
due to the parallel epidemics of obesity and type 2 diabetes.3-11 The reduced delivery volume needed with U-500R
results in fewer total injections for patients receiving high
doses of insulin, which may lead to improved glycemic
control and greater patient satisfaction.8,11,12
The diabetes educator plays a vital role in helping
patients use U-500R successfully. This article provides
information to help diabetes educators feel comfortable as
they guide patients in using U-500R, including an overview of U-500R pharmacology, strategies for outpatient
and inpatient use, and tools to aid in patient education.

Rationale for Use of U-500R

Evidence from controlled clinical trials of diabetes
treatment13-17 provides a clear rationale for maintaining
blood glucose as close as possible to glycemic targets to
reduce the risk of microvascular and cardiovascular complications. Selection of glycemic targets must be individualized to patient characteristics, including age, duration
of diabetes, prevalent cardiovascular disease, and risk of
hypoglycemia and cardiovascular disease.18 There comes
a point when clinicians may be reluctant to increase insulin doses due to practical concerns about delivering large
volumes of insulin, the number of injections required,
and patient adherence to complicated regimens.
Whether patients use a syringe, a pen device, or an
insulin pump, high-volume insulin requirements can create a challenge. Syringes deliver up to 100 units per
injection. Insulin pens have a maximum dose of 60 to
80 units and a total dose per pen of 300 units. Patients
with high-dose insulin requirements may have to use multiple injections per dose with syringe or pens, and pen
users may need to administer partial doses in order to use
all the insulin in the pen. This added complexity may
reduce effectiveness of pen use for some patients. Highdose insulin may be impractical for insulin pump users as
well. For most insulin pumps, the volume of a bolus that
can be given in a single request is limited, often just 25 to
30 units. Because pumps may take as long as 12 to
40 seconds to deliver a unit of insulin, a 30-unit bolus
could take 6 to 20 minutes to deliver, substantially altering the expected profile of rapid-acting insulins.
Use of U-500R has been reported to be cost-effective
on a cost per unit basis in multiple daily injection (MDI)

regimens or off-label use by continuous subcutaneous

insulin infusion (CSII; insulin pumps).7,9,11,19-22 Clinical
case series and retrospective chart reviews have demonstrated significant improvement in glycemic control with
the switch from U-100 insulins to U-500R in highly
insulin-resistant patients.3,5,6,19,21,23-31 No randomized
controlled trials of U-500 efficacy have been completed,
although one is currently in progress.32

Time-Action Profile of U-500R

In a recent pharmacokinetics (PK) and pharmacodynamics (PD) study, 2 clinically relevant doses (50 and
100 units) of U-500R and U-100 regular human insulin
(U-100R) were compared in 24 healthy obese subjects.33
Overall insulin exposure (PK: serum insulin area under the
curve [AUC]) and overall effect (PD: glucose infusion rate
AUC) were similar at both doses and with both formulations. Time-to-onset effect was less than 20 minutes for
both U-500R and U-100R. However, U-500R and U-100R
were not bioequivalent. At both doses, U-100R had measurable activity up to approximately 18 hours, compared
with approximately 20 to 22 hours for U-500R (P values
<.05), with longer early and late time to 50% maximal
effect for U-500R. For the 100-unit dose, U-500R took
longer to reach maximal effect than U-100R (6.4 vs 5.3
hours). These findings support the time action profile of
U-500 insulin as extended prandial (peak effect ~6 hours)
and basal activity (duration of effect approaching
24 hours). They also support the clinical use of U-500R
thirty minutes before meals without concomitant use of
U-100 basal insulin and reinforce the need for vigilance to
prevent late postprandial and nocturnal hypoglycemia.33,34

Clinical Aspects of U-500R Use

Safety

Adverse events reported to Eli Lilly and Company, the

manufacturer of U-500R, are captured in the Lilly Safety
System. Medication errors due to dose confusion between
U-100 and U-500R insulin have resulted in hyperglycemia and hypoglycemia; in rare instances, these errors
have been fatal.8,10 The Institute of Safe Medical Practices
(ISMP) issued a warning in 2007 about increased reports
of medication mix-ups involving U-500R.35 To avoid
medication confusion (and because of expense per 20-mL
vial), most pharmacies will not stock U-500R until it is
needed by a patient.

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Eli Lilly and Company has recently updated the

U-500R package insert34 with storage information for
vials in use; opened vials can be kept unrefrigerated at
temperatures below 30C (86F) for up to 31 days. Lilly
also produces a brochure for health care professionals
that incorporates information from recent publications
about use of U-500R4,7-10 and the revised package insert34
with large, easy-to-read print. New patient education
materials as well as tear sheets for the pharmacist who is
filling the U-500R prescriptions are also available.

Administration and Prescribing

Because there is no syringe or pen calibrated for
U-500R use, U-500R must be administered with either
U-100 insulin syringes or volumetric (tuberculin or
allergy) syringes. U-100 insulin syringes are more commonly used to administer U-500R in the outpatient setting because of greater availability, lower cost, and
smaller needle size.7-10 Given data from studies of dermal
thickness in obese patients, many providers prefer
31-gauge, 6-mm-length needles with U-100 insulin
syringes.36,37 The smallest gauge tuberculin syringe needle is 27 gauge (12.7 mm in length). Patients using these
longer needles should be shown how to pinch a skinfold
and inject at a 90 angle to reduce the risk of intramuscular injection.38
No matter which syringe is selected, it is essential for
the diabetes educator to show patients how to measure
their prescribed dose, using the markings on the syringe
they will use at home. The lack of a syringe or pen device
that is properly scaled to U-500R has made the terminology for prescription writing potentially ambiguous and
confusing (eg, units). Direct patient demonstration is
critical in order to avoid dose confusion and administration errors by the patient. This concern was emphasized
by the FDA Adverse Event Reporting System report in
first quarter of 2008.39
Prescriptions for U-500R should be written based on
the type of syringe the patient will use and should provide both actual units to be administered and amount to
be administered, indicated as respective markings on the
designated syringe. For example, if the patient will be
using U-100 insulin syringes for a U-500R dose of
150 units before meals, write, Human Regular U-500
#vials (for 1- or 3-month supply as applicable); sig: 150
actual units (30 unit markings on U-100 syringe) SC TID
30 minutes before meal. While this method is different

from that stated by the Institute of Safe Medication

Practices in 2001 (which emphasized use of a tuberculin/
volumetric syringe),40 it may be a more logical and practical approach in an outpatient setting and is supported
by the current product package insert content.34 When a
tuberculin syringe is used, 0.3 mL on tuberculin syringe
would be substituted in the above wording.
Patients also need to know how to distinguish U-500R
vials and boxes from those of U-100 insulin, particularly
if the U-500R prescription is new to the patient. Vials of
U-500R contain 20 mL (10,000 units) rather than the
conventional 10 mL (1000 units) for U-100 insulin.
Diagonal brown stripes mark the vial label and box
(Figure 1), making U-500R packaging distinctive in
appearance from U-100R packaging. It is particularly
important for the diabetes educator to teach the patient
how to communicate the dosing regimen to other clinicians (eg, in urgent care or inpatient settings) as recommended in the product package insert (patient
information34). Providing the patient with conversion
tables and formulas8,10,34 or the teaching worksheets provided (Figures 1 and 2) will help the patient understand
the actual insulin dose as well as the dose in unit markings on the U-100 insulin syringe or volume (milliliters)
on a tuberculin/volumetric syringe. These teaching worksheets may be used to document standard doses for each
meal. Some providers may prefer to prescribe a modified
correction dose regimen of U-500R that allows for
adjusting the dose in the event of abnormally low or high
premeal blood glucose concentrations. A modified correction dose regimen can also be indicated on these
worksheets.

Teaching Tools for the Use of

U-500R
Before a patient begins treatment with U-500R, the
patients daily insulin requirements must be carefully
assessed. Patients should be asked how often they skip
meals and asked to demonstrate how they perform their
current injections. If a patient is having difficulty taking
the required number of U-100 insulin injections, the
patient may actually be taking less insulin than prescribed. Patients requiring a total daily dose (TDD) of
U-100 insulin greater than 200 units with MDIs or greater
than 150 units (approximately 3 units per hour basal
rate8) delivered by an insulin pump (off-label use) may
benefit from U-500R.

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The Diabetes EDUCATOR

156

Getting Started with Humulin R U-500 Insulin

What is it?

It is regular insulin 5 times more concentrated than your U-100 insulin.

(This means 500 units in one milliliter instead of the typical 100 units in one milliliter).

Why do you need it?

For large doses of insulin, it helps to be able to get the right dose without taking large volumes.

How does it work?

It starts working in the first hour after injection and lasts up to 12 to 24 hours.

How can it be taken?

You will use a U-100 insulin syringe

Example: if your diabetes care team wants you to get 100 units of insulin, draw up to the 20unit marking on a U-100 insulin syringe, because
the U-500 insulin is 5 times more concentrated than U-100 insulin.

Using a U-100 Insulin Syringe

Syringe size ___________
Your actual Insulin dose: ________ units
You draw up _______ unit markings.
Low Blood Glucose (low blood sugar = hypoglycemia)
If you have a headache, or feel shaky, sweaty, weak, or nervous, you may have low blood
glucose. Check your blood glucose, if possible, and if it is below 80, take one of the following
treatments and wait 15 minutes. If you dont feel better, repeat:

3-5 glucose tablets

1 cup of milk

cup of real soda pop (not sugar free)

cup of juice

Discuss whether you should be prescribed a glucagon emergency kit with your physician/diabetes treatment team

Getting the Correct Dose of Humulin R U-500

Your U-500R comes in 20-mL vials containing 10,000 units (U-100 insulin vials are typically 10-mL with
1000 units) and U500R has brown diagonal stripes on the box and bottle label. Humulin R U-100 vial
and box (white, blue and yellow) are also shown here for comparison. Check your insulin before you
leave the pharmacy to be sure you have the correct insulin.
Humulin R U-500 is 5 times more concentrated than your U-100 insulins, so every unit marking of
U-500R drawn on an insulin syringe is the same as 5 units of your usual U100 insulin. It is important to
understand your dose and the amount to draw up in the syringe to be sure you get the correct dose.
Pre-meal dose of U-500R based on pre-meal blood sugar:
PRE-BREAKFAST
Blood sugar

Insulin U-500R to Inject 30 minutes pre-meal

(Each vial contains 500 actual units of insulin/mL;
1 unit marking on aU-100 insulin syringe contains 5 units U-500R)

Actual units of
insulin

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

> ____

_____ unit markings

= _____ units

____ - ____

(continued)
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157

PRE-LUNCH Blood
sugar

Insulin U-500R to Inject 30 minutes pre-meal

(Each vial contains 500 actual units of insulin/mL;
1 unit marking on a U-100 insulin syringe contains 5 units U-500R)

Actual units of
insulin

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

> ____

_____ unit markings

= _____ units

Insulin U-500R to Inject 30 minutes pre-meal

(Each vial contains 500 actual units of insulin/mL;
1 unit marking on a U-100 insulin syringe contains 5 units U-500R)

Actual units of
insulin

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

_____ unit markings

= _____ units

____ - ____

_____ unit markings

= _____ units

> ____

_____ unit markings

= _____ units

____ - ____

PRE-Dinner Blood
sugar

____ - ____

____ - ____

Other Instructions:
Diabetes Care Team Member Name: Date:__________________

Figure 1. Two-page U-500 regular insulin teaching worksheet for use with a U-100 insulin syringe (developed by V. Valentine).

Formulating a Regimen

Because U-500R has both basal and prandial properties,33,34 most patients can take it exclusively without
addition of U-100 basal insulin,8,10 although 2 case series
have reported combined use of prandial and/or basal
U-100 insulins with U-500R.29,30 Figure 3 shows theoretical graphs that may be useful in explaining to patients
how bolus doses earlier in the day may lead to a significant amount of insulin on board, which then affects the
needed evening meal bolus dose. The AUC depicts

insulin on board or the tail of persisting U-500R. The

effect of the later bolus dose shows why a differing distribution or weighting of doses may be necessary for many
patients depending on their individual responses and selfmonitored blood glucose (SMBG) results.
Table 1 contains an algorithm showing how a U-500R
regimen may be proportioned and dosed as well as how
a U-100 insulin regimen can be converted to U-500R.7-11
Dose-for-dose conversion is recommended for patients
with baseline A1C values between 8% and 10%. For
patients with A1C 8%, the insulin dose may be reduced

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The Diabetes EDUCATOR

158

Getting Started with Humulin R U-500 Insulin

What is it?

It is regular insulin 5 times more concentrated than your U-100 insulin.

(This means 500 units in one milliliter instead of the typical 100 units in one milliliter).

Why do you need it?

For large doses of insulin, it helps to be able to get the right dose without taking large volumes.

How does it work?

It starts working in the first hour after injection and lasts up to 12 to 24 hours.

How can it be taken?

You will use a tuberculin/volumetric syringe

Example: if your diabetes care team want you to get 100 units of insulin, you will draw up to the 0.2 mL marking on a tuberculin syringe

Using a Tuberculin/Volumetric Syringe

Your actual Insulin dose: ________ units
You draw up _______ mLs
Low Blood Glucose (low blood sugar = hypoglycemia)
If you have a headache or feel shaky, sweaty, weak, or nervous, you may have low blood glucose.
Check your blood glucose, if possible, and if it is below 80, take one of the following treatments
and wait 15 minutes. If not feeling better, repeat:

3-5 glucose tablets
cup of real soda pop (not sugar free)

1 cup of milk
cup of juice
Discuss whether you should be prescribed a glucagon emergency kit with your physician/
diabetes treatment team

Getting the Correct Dose of Humulin R U-500

Your U-500R comes in 20-mL vials containing 10,000 units (U-100 insulin vials are typically 10-mL with
1000 units) and U500R has brown diagonal stripes on the box and bottle label. Humulin R U-100 vial
and box (white, blue and yellow labels) are also shown here for comparison. Check your insulin before
you leave the pharmacy to be sure you have the correct insulin.
Humulin R U-500 is 5 times more concentrated than your U-100 insulins, so every 0.01mL of U-500R
drawn on a tuberculin syringe is the same as 5 units of your usual U-100 insulin. It is important to
understand your dose and the amount to draw up in the syringe to be sure you get the correct dose.
Pre-meal dose of U-500R based on pre-meal blood sugar:
PRE-BREAKFAST
Blood sugar

Insulin U-500R to Inject 30 minutes pre-meal

(Each vial contains 500 actual units of insulin/mL; 0.01 mL on a tuberculin syringe
contains 5 units U-500R)

Actual units of
insulin

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

> ____

0.___ mLs

= _____ units

____ - ____

(continued)
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159

PRE-Lunch Blood
sugar

Insulin U-500R to Inject 30 minutes pre-meal

(Each vial contains 500 actual units of insulin/mL; 0.01 mL on a tuberculin syringe
contains 5 units U-500R)

Actual units of
insulin

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

> ____

0.___ mLs

= _____ units

Insulin U-500R to Inject 30 minutes pre-meal

(Each vial contains 500 actual units of insulin/mL; 0.01 mL on a tuberculin syringe
contains 5 units U-500R)

Actual units of
insulin

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

0.___ mLs

= _____ units

____ - ____

0.___ mLs

= _____ units

> ____

0.___ mLs

= _____ units

____ - ____

PRE-DiNNER Blood
sugar

____ - ____

____ - ____

Other Instructions:
Diabetes Care Team Member Name:
Date:

Figure 2. Two-page U-500 regular insulin teaching worksheet for use with a tuberculin/volumetric syringe (developed by V. Valentine).

by 10% to 20%. For patients with A1C 10%, a 10% to

20% dose increase should be considered.8,10,11
Most patients are treated with injections 2 or 3 times
per day.5,6,8,10,11,27,28,34 For twice-daily doses, use blood
glucose readings before lunch and evening meal to adjust
the morning dose and use blood glucose readings at bedtime, overnight, and fasting the next morning to adjust
the evening meal dose. For doses injected 3 times per day
before meals, use lunchtime blood glucose readings for
morning dose adjustments, evening meal blood glucose

readings for lunch dose adjustments, and after-dinner and

before-breakfast blood glucose readings for evening
meal dose adjustments. Patients should periodically
check blood glucose readings early morning (2 or 3 am)
after dose increases or if a small bedtime dose is added
(4 times per day dosing7-11) to monitor for nocturnal
hypoglycemia based on the long duration of U-500R.33
Bedtime snacks are generally not recommended since
they would add to the already excessive evening caloric
burden of the typical patient requiring U-500R. Sick

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Figure 3. Theoretically depicted time-action profiles of human U-500 regular insulin (U-500R). For both graphs, the area under the curve represents the
amount of remaining insulin. 8A indicates 8 am. (A) Three daily doses of
insulin. (B) Two daily doses of insulin.

days, alteration in meal timing and carbohydrate distribution, and correction scales all may increase the risk of
hypoglycemia, which can occur 18 to 24 hours after the
insulin is injected.34 The use of glucagon should be
included as part of the patient teaching.
Use With Insulin Pumps

Delivery of U-500R by an insulin pump has not been

approved by the FDA. However, case reports and series
have described an improvement in A1C when U-500R
was delivered by an insulin pump in patients with suboptimal glycemic control who require large doses of insulin.19,23-26,31,41 Reduced leakage at the infusion set
insertion site has been reported.23 No catheter occlusions
were reported in these studies,19,23-26,31,39 possibly attributable to the limited need for low-flow infusion rates
with U-500R.42 The largest case series (N = 59; mean
duration of treatment 49 months) reported severe hypoglycemia rate of 0.1 episodes per patient per year (SMBG

50 mg/dL or self-reported episode requiring assistance)

with 2 hypoglycemia episodes resulting in hospitalization.31 Patient satisfaction has been reported to be favorable in some clinical case series of U-500R administration
by insulin pump,23,25 and positive clinical experience has
also been reported.21
For patients whose insulin-pump-delivered U-100
insulin basal needs are 3 units per hour or more, the
switch to U-500R will substantially reduce time-consuming and costly pump cartridge (current reservoirs 1.8-3.0
mL) and infusion set changes.8,19 It may also extend
pump battery life and save money on replacement batteries.8 Initial dose conversion from U-100 insulin can be
adjusted according to A1C (Table 1, footnote b). Some
experts make greater dose reductions in anticipation of
better insulin absorption attributable to the lower volume
needed with U-500R.8,24,25 Because insulin pumps do not
have software that can correct for delivery of U-500R
rather than U-100 insulins, a patients programmed doses
must be divided by 5 to obtain the TDD delivered in
pump units.8,10,23 Half of this TDD is divided by 24 to
obtain the hourly basal rate, while the other half is
administered as premeal bolus doses (Table 1).8,10 It may
be useful to place a label with dosing information
directly on the pump for the benefit of the patient and
other clinicians (eg, in urgent care or inpatient settings).
If hypoglycemia is a particular concern, the nocturnal
basal rate can be reduced 20% beginning between 9 pm
and midnight. Interprandial correction doses are not recommended when U-500R is delivered by either insulin
pump or MDI to avoid stacking. Based on the PK/PD
study of single-dose U-500R in obese subjects without
diabetes,33 at least 6 hours may be entered for the insulinon-board function with insulin pumps, and bolus doses
are recommended 30 minutes before a meal. Carbohydrate
counting/insulin dosing may be used, but according to
current evidence, fixed dosing according to the proportion
of carbohydrates ingested per meal may also be used.8,11,21

Inpatient Use of U-500R

The difficulties of managing U-500R treatment may be
magnified in the inpatient setting if practitioners without
U-500R experience participate in the patients clinical
care. It is recommended that hospitals have institutional
policies for use of U-500 insulin in the inpatient setting.8,10,43-45 These policies should define where U-500R
will be stored in the pharmacy and/or nursing unit. The

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Table 1

Algorithm for U-500 Regular Insulin Dosinga

Insulin Daily Doseb

Injection, Frequency, Schedule, Deliveryc

150-300 units per day

Twice daily (before breakfast and supper)

3 times daily (before meals)
Via insulin pump (1 pump unit = 0.01 mL; 0.01
mL of U-500R insulin = 5 actual units)
3 times daily
4 times daily (before meals and bedtime)
Via insulin pump

300-600 units per day

>600 units per day

4 times dailye

Guide for How Doses Are Divided Daily via

Percentage of TDDd
60/40 or 50/50
40/30/30 or 33.3/33.3/33.3
Three mealtime boluses (50% of TDD) with basal
rate (50% of TDD)
40/30/30 or 33.3/33.3/33.3
30/30/30/10
Three mealtime boluses (50% of TDD) with basal
rate (50% of TDD)
30/30/30/10

Abbreviation: TDD, total daily dose.

a
Simplified algorithm for conversion from previous TDD of U-100 insulins to U-500 regular insulin (adapted from Lane et al8).
b
When switching to U-500 regular insulin, the TDD may be reduced by 10% to 20% for initial A1C 8%. Consider increasing the dose by 10% to 20% for initial A1C 10%.
c
U-500 regular boluses are recommended 30 minutes before a meal; titrate dosage according to frequent self-monitored blood glucose.
d
May initially use fixed ratios or distribute boluses according to the proportion of carbohydrates with meal or carbohydrate-counting according to patient preference and
physician judgment.
e
Do not inject more than 2 mL at any one injection site.7

policy should dictate whether the syringe is filled in the

pharmacy or on the patient care unit, how U500R should
be prescribed, and how it should be administered.
Medication selection errors have been reported to occur
most often when insulin was selected from a list on a computerized information system and U-500R was directly
next to and not well differentiated from U-100 insulin. In
hospital information systems, it is recommended that the
name U-500R be preceded by the word concentrated in
uppercase letters to avoid selection errors.4 In addition,
restrictions may be put in place to allow only qualified
hospital staff to prescribe U-500R.10 Preprinted order sets
or electronic order sets can also help prevent errors.
An experienced diabetes educator who understands the
use of U-500R should be involved in the care of any patient
receiving U-500R, especially during high-risk periods such
as admission and discharge. Frequent blood glucose assessment including nocturnal blood glucose checks, adjustments in the U-500R regimen, and use of hypoglycemia
protocols is important,10,43 Given the extended duration of
action of U-500R, standard hospital hypoglycemia protocols may need to be modified since hypoglycemic episodes
with U-500R may recur after initial treatment. Depending
on the timing of the last insulin dose and cause of the hypoglycemic event, hypoglycemia can be prolonged and may

require continuous intravenous dextrose supplementation

with careful follow-up blood glucose testing with patients
who are not eating.
Determining a Patients Home Regimen
of U-500R

Because U-100 insulin is the current standard, patients

and health care providers may experience confusion
about U-500R dosing. Misinterpretations during medication reconciliation can occur. Patients often report home
doses in unit markings measured on a U-100 insulin
syringe, which may give the impression that their insulin
dose is 5-fold lower than it actually is. A risk of overdosing occurs when patients report actual units prescribed
and this is misinterpreted as unit markings on an insulin
syringe (resulting in administration of a dose 5-fold
higher than needed). This problem is not unique to insulin. Patients taking oral medications often know the
names and/or colors of the pills they take but not necessarily the milligram strength of the pills.
Diabetes educators play a critical role in helping
patient care teams understand the U-500R regimen by
interviewing the patient and collecting the correct information. Home dose verification by patient demonstration

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162

Scan to pharmacy and place in progress note sec on of chart

Dose & syringe must be verified prior to dispensing medica on

Pa ent or care provider demonstrated and discussed measuring to the marks described for each dose below:
Pa ent uses INSULIN SYRINGE at home dose reported as
Unit markings measured on an INSULIN syringe

Pa ent uses a TUBERCULIN SYRINGE at home

dose reported in volume (mL)

 Breakfast Dose:

 Breakfast Dose:

5 X _______ unit markings on an INSULIN SYRINGE =

500 X _______ mL =

units U=500 insulin administered

 Lunch Dose:

units U=500 insulin administered

 Lunch Dose:

5 X _______ unit markings on an INSULIN SYRINGE =

units U=500 insulin administered

500 X _______ mL =
units U=500 insulin administered

 Dinner Dose:

 Dinner Dose:

5 X _______ unit markings on an INSULIN SYRINGE =

500 X _______ mL =

units U=500 insulin administered

units U=500 insulin administered

 Bedme Dose:

 Bedme Dose:

5 X _______ unit markings on an INSULIN SYRINGE =

500 X _______ mL =

units U=500 insulin administered

units U=500 insulin administered

 Paent uses blood glucose based dosing described below:

Blood Glucose
(mg/dL)

Unit Markings
Measured on a
U-100 Insulin Syringe

Volume of U-500
Insulin (mL) Measured
on Volumetric Syringe

Actual Units of Insulin

Unit markings X 5
Volume (mL) X 500

 Doses confirmed as described above.

 Doses confirmed with previous instuon and listed above.
 Unable to obtain demonstraon/verificaon. NOTE: It is strongly recommended to begin insulin

Concentrated U-500 insulin Home Dose Verificaon

THIS IS NOT AN ORDER

infusion AND consult endocrinology

Date: _____________ Time:________ VERIFIED BY: ______________________________________________

USE BALL POINT PEN. PRESS FIRMLY.

Figure 4. Human U-500 regular insulin home dose verification form.

is the most reliable method for determining home U-500R

doses. During the verification process, patients are provided the syringe used at home for measuring insulin and
are asked to demonstrate how each dose of insulin is
measured. The diabetes educator observes the patient and
verifies each dose by inspecting the syringe. If a diabetes
educator is not available, this may also be done by a pharmacist or other practitioner familiar with U-500R.

The authors have developed a tool that can be used to

record the volume of U-500R the patient needs to inject
and to convert it to the actual unit dose of insulin administered (adapted from Samaan et al44). This tool (Figure
4) can assist in determining the patients home regimen
of U-500R and ensuring that it is correctly recorded in
the medical record for accurate medical reconciliation.
This tool can also serve as a helpful intake form when

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doses must be modified at admission because of significantly low or high blood glucose levels.
When interviewing patients for home dose verification, diabetes educators can ask about eating habits and
average blood glucose measurements including hypoglycemic levels and events. This valuable information can
be passed on to the patient care team to determine
whether an initial dose reduction is indicated. Because of
changes in caloric intake and activity, blood glucose
should be monitored closely and include a nocturnal
check for hypoglycemia.
U-500R Administration Schedule, Diet,
and U-500R Dosing Adjustment in the
Inpatient Setting

Patients who are not eating or who receive parenteral

or enteral nutrition should not be treated with U-500R.
Most patients can be safely managed with a continuous
intravenous insulin infusion, and some patients may be
effectively managed with traditional basal bolus regimens using U-100 insulins.46,47 U-500R should only be
administered to inpatients with uninterrupted meals.
Dosing U-500R 30 minutes before meals is ideal (given
the onset of action), and cautious correction dosing
according to a patients expected insulin sensitivity can
be done. Use of interprandial correction doses is not recommended given the risk of stacking.8,10 When hospital policy allows for patient use of U-500R by CSII, these
same considerations generally apply.
Implementation of a calorie-controlled diet in the
inpatient setting for obese patients may result in lowered
insulin requirements.45 The provider needs to be aware of
the potential reduction in insulin requirements so that the
insulin regimen can be adjusted and hypoglycemia prevented. In recent experience at the National Institutes of
Health (E. Cochran and P. Gorden, MD, e-mail communication, July 2012), approximately 15 obese patients
requiring high-dose insulin for treatment of type 2 diabetes had major reductions in total daily dose during hospitalization and inpatient initiation of a mild weight loss
diet. Insulin requirements in this small hospitalized
cohort decreased 50% to 70% within 24 to 48 hours of
dietary implementation. Empiric reduction of insulin
TDD by at least 50% or glucose-based insulin dosing at
admission is a reasonable approach to avoid hypoglycemia in the inpatient setting.

The Role of the Diabetes Educator

During Hospital Discharge

Because hospital formulary policies for U-500R predominantly use tuberculin/volumetric syringes (milliliter
markings)44,45 and U-100 syringes are the most often used
syringes in outpatient settings (apart from Veterans
Administration facilities), instruction (or reinstruction)
on the use of U-100 insulin syringes may be needed at
discharge. Upon reviewing the conversion of actual units
of U-500R to measured unit markings on a U-100 syringe,
the diabetes educator can also ensure that take-home
instructions and prescriptions include actual units of
U-500R in addition to the U-100 syringe unit markings.
Given the cost of the U-500R vial (containing 10,000
units of insulin), hospital pharmacy relabeling for home
use and dispensing of the in-use U-500R vial at discharge
may be warranted, when allowed by state law and pharmacy policies.
When U-500R Is Not Available Through
the Inpatient Pharmacy

When U-500R is not available through the inpatient

pharmacy, alternative management with basal bolus
U-100 therapy or intravenous administration of U-100
insulin as previously described is recommended. Merely
advising a U-500R-treated patient to take his or her
U-500R vial to the hospital for floor use upon admission
is not sufficient for safe use. When hospital policy allows
for a patients own medication use, a U-500R administration policy must be in place to address storage, prescribing, and administration. Clinical studies are needed to
address optimal insulin management when patients who
require high-dose insulin are hospitalized.

Summary
U-500R is useful for treating patients with any type of
diabetes who require high doses of insulin. U-500R alleviates the volume-related problems associated with high
doses of U-100 insulin, making treatment with high doses
of insulin more feasible, with fewer injections for
patients, as well as more cost-efficient and potentially
more effective based on reported clinical case series and
our experience. The tools described in this article can be
useful to diabetes educators in assisting patients with

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U-500R regimens in both outpatient and inpatient settings. These tools, which the authors have used successfully for years, can help diabetes educators feel more
comfortable and confident as they advise and manage the
treatment of patients receiving U-500R as part of their
overall diabetes care plan.
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