Embracing Concentrated Insulins: With a Focus On Humulin R U-500

The number of concentrated insulin products available to treat patients with diabetes has expanded over the last several years in the United States (table ).^1-4 These products contain a greater number of units of insulin in each milliliter than standard U-100 insulins and may provide options for patients to improve glycemic control with treatment regimens that may enhance their adherence to therapy.⁵ All concentrated insulins are available in distinctive prefilled pen devices for simple product recognition and accurate dose administration. In addition, a new dedicated BDTM U-500 insulin syringe must be prescribed to administer human regular insulin U-500 (U-500R) from the multiple dose vial.⁴

Findings from recent market research among pharmacists and other health care professionals identified a need for a deeper understanding of all concentrated insulins.⁶ Increased knowledge of concentrated insulins among pharmacists would expand clinical skills and address patient safety in the use of these agents, especially U-500R. Pharmacists should be able to recognize the appropriate use of, risks involved with, and the best practices for prescribing, dispensing, and patient education on concentrated insulins. This article discusses concentrated insulins; who may be the appropriate patient; the transition from U-100 insulin therapy; clinical considerations, with a deeper focus on U-500R; and the challenges and opportunities for pharmacists within the insulin prescription journey.

WHY DO SOME PATIENTS WITH DIABETES NEED CONCENTRATED INSULINS?

The American Diabetes Association⁵ and the American Association of Clinical Endocrinology⁷ suggest continuous titration of insulin to meet hemoglobin A1C goals, but do not give specific guidelines for concentrated insulins. There is a simple answer to the question, “Why do some patients with diabetes need a concentrated insulin?” Because it allows for the administration of more units of insulin in less volume than the standard U-100 concentration. This is particularly important when higher doses of insulin are needed to treat insulin resistance and achieve glycemic control in patients with more progressive diabetes. As the dose of U100 insulin increases so does the injection volume, thereby the days’ supply for a pen or vial lessens. For some patients, their insulin dose could substantially reduce the days’ supply for a U-100 pen from several days to just over a day, requiring more planning on the part of the patient to schedule an insulin supply with such a short duration. Other challenges associated with the administration of high-dose, high-volume U-100 insulin include injection site discomfort and more daily injections, both of which can lead to low adherence to therapy.⁸

Fortunately, all concentrated insulins are available in a prefilled pen calibrated to deliver the prescribed dose in units by dialing to the number of insulin units to be injected.^1-4 Moreover, the dedicated BD U-500 insulin syringe eliminates the need to deliver U-500R from the multiple dose vial by U-100 insulin or tuberculin (volumetric) syringe.⁴ These delivery devices should reduce the risk for dosing errors. Some concentrated insulin pens require less injection force to administer a dose, which may assist patients with limited hand mobility.^9-11 The lower injection volume to deliver a dose can help reduce the pain associated with injecting higher doses of U-100 insulins.⁸ Surveyed patients generally preferred higher concentration insulin pens to U-100 insulin pens.^12,13

WHO IS THE APPROPRIATE PATIENT FOR CONCENTRATED INSULIN?

If a patient’s insulin needs on U-100 insulin can be met with a concentrated insulin that is used within the manufacturer’s product expiration date and indication for use, that patient should be considered. In most cases, if the pharmacist is dispensing 2 or more packs of prefilled insulin pens or vials of a U-100 prandial (mealtime) insulin and/or a basal insulin for a 30-day supply, the patient may benefit from converting to a concentrated insulin. As with any glucose-lowering therapy, the decision to use a concentrated insulin should include consideration for the patient’s risk of hypoglycemia, individual preferences, and financial circumstances.⁵

Bioequivalent Concentrated Insulins (Insulin Degludec, Insulin Lispro)

Bioequivalence of the tested drug to the listed reference drug is defined by the FDA as showing “no significant difference in the rate and extent of absorption of the active pharmaceutical ingredient.”¹⁴ No difference would be expected in the pharmacokinetics or pharmacodynamics of a bioequivalent concentrated insulin to the respective U-100 counterpart (table). Insulin lispro1 or insulin degludec2 requires no dosage adjustment when transferring a patient from one concentration to another, since the respective U-100 and U-200 formulations are bioequivalent. Insulin degludec offers an extended time-action profile allowing for flexibility in timing of administration as well as less injection volume for patients on high doses of insulin.^2,15 The insulin lispro U-200 pen offers double the pen-device capacity¹ to provide the convenience of fewer pens per month for patients.

Non-bioequivalent Concentrated Insulins (Insulin Glargine, Human Regular)

Higher concentration insulins are not bioequivalent to their U-100 counterpart (table), as the time-action profile of insulin changes with concentrations of U-300 or more.^16,17 U-500R and U-300 glargine are not bioequivalent to their U-100 counterparts and may require an adjustment of the total daily dose (TDD) of insulin when transitioning from one concentration to another. The TDD of insulin glargine³ may need to be increased when transitioning from U-100 to U-300 and the TDD of U-500R^18,19 may need to be decreased when transitioning from U-100 insulins. Insulin glargine U-300 offers an extended time-action profile allowing for a stable response.^3,20 U-500R provides 80% less injection volume than U-100 insulin⁴ and can be dosed as monotherapy with 2 or 3 injections per day due to its prandial-basal action.^16,18

WHAT ARE THE SAFETY CONCERNS WITH CONCENTRATED INSULIN?

As with all insulins, hypoglycemia is the primary safety concern with concentrated insulin therapy.^7,21 Glycemic targets must be individualized to minimize the frequency and severity of hypoglycemic episodes. Patients and their family members or other supporters should be taught to recognize the signs and symptoms of hypoglycemia and how to manage hypoglycemic episodes, including when and how to administer glucagon.²¹

Insulin glargine U-3003,²⁰ and both formulations of insulin degludec^2,22 are basal insulin analogues with flatter and more prolonged time-action profiles than insulin glargine U-100. These agents may reduce the risk for hypoglycemia from basal insulin therapy. Lower rates of hypoglycemia, particularly nocturnal hypoglycemia, were observed in randomized titration-to-target trials comparing these newer basal insulins with insulin glargine U-100 in patients with type 1^23,24 or type 2^25-28 diabetes.

Insulin lispro U-200 is bioequivalent to its standard U-100 formulation, and therefore the risk for hypoglycemia between the two concentrations of this rapid-acting insulin analogue is expected to be the same.¹

WHO IS THE APPROPRIATE PATIENT FOR HUMAN REGULAR INSULIN U500?

Adult and pediatric patients who require over 200 units of insulin a day to improve their glycemic control may be candidates for U-500R therapy.⁴ Patients who may not be appropriate for U-500R therapy are those who are at high risk for hypoglycemia, not reliable to test glucose, do not eat predictable meals (allowing for dosing 30 minutes before meals), or have difficulty following directions.^4,19 Patients treated with U-500R should be able to recognize hypoglycemia events, monitor their blood glucose, and attend office visits. A person of extreme age with major chronic debilities, cognitive or psychiatric impairment, or extreme meal patterns (ie, one meal per day or excessive grazing) may not be appropriate for U-500R.

U-500R is indicated for use as insulin monotherapy.⁴ When administered subcutaneously 2 or 3 times each day, U-500R provides basal and mealtime coverage without the need for another insulin,^4,16,18,29 unlike human regular insulin U-100 that provides only mealtime (or bolus) coverage.³⁰ Insulin monotherapy with U-500R reduces the complexity of insulin therapy, particularly with twice-daily dosing. If you are transitioning a patient from U-100 insulin to U-500R, consider the following:

• The prescription should clearly designate the dose in insulin units, not unit markings.4
• Review the patient’s profile to assess if detailed counseling is needed. Establish that the insulin units prescribed are correct (should be within the range of 80% to 100% of the prior U-100 insulin TDD18,19).
• If the prescription is written for a U-500R KwikPen, do not substitute with the U500R vial. The patient should have been educated on the pen. If not, this is a good opportunity for the pharmacist to provide education.
• If a patient is prescribed a vial of U-500R, the dedicated BD U-500 insulin syringe must also be prescribed to avoid medication errors.4 (A separate prescription for the syringe is required). Do not dispense the U-500R vial with U-100 insulin or tuberculin (volumetric) syringes without first verifying with the prescriber, as dosing errors may occur. Off-label use of U-100 insulin or tuberculin (volumetric) syringes with U-500R should be clearly documented by the prescriber and within the pharmacy system.
• Communicate to the patient to stop mealtime and basal insu- lins previously prescribed. Although some prescribers may choose to continue other insulin therapy with U-500R, this has not been studied.4 Therefore, off-label concomitant use of other insulins with U-500R should be clearly documented by the prescriber and within the pharmacy system.
• Educate patients on their injection method. For some, this may be the first time using an insulin pen.
• Do not count clicks of the dose knob to select dose.4 The U-500R KwikPen dials in 5 insulin units with each click. Patients who rely on the click sound of a prefilled pen to determine their insulin dose, such as the visually impaired or blind, should receive assistance from another person who has been taught how to administer U-500R.

WHAT ARE THE CLINICAL CONSIDERATIONS FOR PRESCRIBING HUMAN REGULAR INSULIN U-500?

Time-Action Profile of U-500R

The basal-bolus activity of U-500R is unique and attributed to its high concentration.⁴ Steady state is reached in 24 hours with twice-daily or thrice-daily subcutaneous administration.²⁹ Mean time to effect is less than 15 minutes and mean duration of action is 21 hours (range, 13-24) after doses of 50 units (0.4-0.6 units/kg) and 100 units (0.8-1.3 units/kg).⁴ Although bioavailability (absorption from the injection site) and time to effect are similar between the U-100 and U-500 concentrations of human regular insulin at these higher doses, their time-action profiles are not equivalent.¹⁶ U-500R has a greater delay in peak effect, with a lower, more gradual decline in concentration, and prolonged duration of action.

Administration of U-500R

U-500R administered either twice-daily or thrice-daily showed clinically equivalent efficacy and safety in a randomized titration-to-target trial.18 Despite demonstrated equivalence between efficacy and safety with the 2 U-500R dosing regimens, pro- viders may consider titration, complexity, injection burden, and hypoglycemia risk when determining which of these dosing regimens to prescribe. Twice-daily administration means less injection burden and simpler titration to dosing 3 times each day. However, administration 3 times a day resulted in slightly fewer nonsevere hypoglycemia events, particularly at night. Most patients can dose twice-daily,^18,31 including those who need larger insulin doses still within the maximum dosing limits of the prefilled pen (300 units/dose) or dedicated U-500 syringe (250 units/dose).⁴ Patients using U500R twice-daily who experience frequent overnight hypoglycemia or significant after meal excursion patterns, despite eating lunch and making adjustments to the breakfast dose, should be considered for thrice-daily dosing.¹⁹

Bergen and colleagues¹⁹ published clinically relevant recommendations and teaching materials for the optimal management of patients treated with U-500R. The initiation and titration algorithms used in the U-500R titration-to-target trial18 were adapted by the authors for the clinical practice setting and are summarized below:

• Confirm the TDD of U-100 insulin to identify poten- tial nonadherence with previous therapy before initiating U-500R.
• Start U-500R at 20% of the confirmed U-100 TDD. Use conventional rounding to the nearest 5 units to calculate TDD.
• Administer U-500R approximately 30 minutes before meals. Initially divide the TDD into 60:40 (%) proportions for twice- daily dosing (morning:evening) or 40:30:30 (%) proportions for thrice-daily dosing (morning:midday:evening).
• Titrate all premeal doses based on the 7-day mean premeal blood glucose reading of the subsequent meal. For pre-eve- ning meal adjustments, also consider bedtime and 3:00 AM blood glucose readings (prioritize hypoglycemia over hyperglycemia).
• For hyperglycemia, increase the premeal dose by 5% (131- 180 mg/dL [7.27-9.99 mmol/L]), by 10% (181-230 mg/dL [10.05-12.77 mmol/L], or by 15% (>230 mg/dL [>12.77 mmol/L]).
• For hypoglycemia, decrease the premeal dose by 10% (<80 mg/dL [<4.44 mmol/L).
• For blood glucose readings of 80-130 mg/dL (4.44-7.22 mmol/L), no dose adjustment is required.

WITHIN THE INSULIN PRESCRIPTION JOURNEY FROM PRESCRIBER TO PHARMACIST TO PATIENT, WHAT CHALLENGES OR OPPORTUNITIES COME TO MIND?

In today’s world of e-prescribing, the ability to prescribe, read all elements of a prescription, process, and dispense should be easier. Despite this advancement in technology, prescribing systems are not standardized, not ideal, and can cause confusion for the prescriber and pharmacist. Although not an exhaustive list, key considerations for prescribing systems and counseling patients to mitigate prescribing and dispensing errors follow.

Prescribing Systems

Ensure that electronic medical records (EMRs) clearly show all insulin options with enough detail for prescriber selection by brand name, nonproprietary name, concentration, and type. The following are suggestions for enhancing prescribing systems:

• Provide clear prescription instructions, including total daily units and units of insulin for each injection. This allows for patient counseling and days’ supply calculations, which should include priming of pens.
• Include, when warranted, co-dispensed messages regarding pen needles and syringes (eg, BD U-500) with the prescription.
• With the introduction of follow-on biologics and biosimilars, EMRs should e-prescribe the product with the intended brand name rather than the non-proprietary name alone, along with the concentration (eg, Tresiba U-200 vs Tresiba U-100 or Humalog U-200 versus Humalog U-100). Including the proprietary name will reduce patient, pharmacist, and prescriber confusion about which product to dispense and will facilitate payer coverage.

Patient Counseling

All patients on insulin, regardless of concentration, should be counseled on the first and second fill for a clear understanding of their therapy. Patients and pharmacists should not be complacent when transitioning from standard U-100 insulin to a concentrated insulin. To mitigate patient confusion and improve patient safety, consider uploading hard counseling edits within the EMR and pharmacy systems. All patients on insulin should become part of the first-fill phone list being implemented in many practice settings. Consider utilizing patient education tools from advocacy groups (eg, American Association of Diabetes Educators or American Diabetes Association) or insulin manufacturer resources to assist with the counseling process. Most manufacturers have educational materials in print, online, and available through mobile apps that can be downloaded in the pharmacy on the patient’s mobile device. In pharmacy settings where the workflow is not designed for lengthy patient counseling sessions, encourage patients to see a diabetes educator on a regular basis. Some pharmacies have a diabetes education program on site, but, if not, suggest the patient request a referral from the prescriber to a diabetes education center.

As with any medication, adverse effects can occur with insulin use. Hypoglycemia is the most common. Therefore, managing hypoglycemia is important for pharmacists to discuss with patients. Ensure patients know the signs and risks of hypoglycemia,as well as associated treatment options. Treatment recommendations for hypoglycemia in conscious patients emphasize the recognition of symptoms and treatment with fast-acting carbohydrates followed by blood glucose monitoring until blood glucose returns to normal.²¹ For severe hypoglycemia, glucagon may be administered.³² Despite their risk for hypoglycemia, many patients do not know about the need to have a glucagon emergency kit. Pharmacists have the knowledge to educate patients and caregivers on glucagon administration and should consider requesting a prescription for glucagon from the prescriber for their patients on insulin.

Patients who are prescribed a concentrated insulin may not have received education in the prescriber’s office on the use of a prefilled pen or the required dedicated BD U-500 insulin syringe. The pharmacist should first assess the patient’s competency in using either of these devices, as applicable. For patients who have used a U-100 insulin or tuberculin (volumetric) syringe to administer U-500R from a vial, stress that no calculation is needed to administer U-500R by either the dedicated insulin syringe or prefilled pen, as both display the number of insulin units to be injected. As previously noted, using a U-100 insulin or tuberculin (volumetric) syringe to administer U-500R from the vial is an considered off-label use and should be discouraged to avoid medication errors.

A pharmacist can help to reduce the costs associated with insulin therapy, which may be a barrier to adherence to therapy. Discuss the option of discount cards, co-pay cards, and patient assistance programs with patients who qualify.

CONCLUSIONS

For patients with diabetes who require higher doses of insulin to achieve glycemic control, concentrated insulins should be considered, because these patients are already taking high doses of standard U-100 insulin. Regardless of the concentration of insulin, the number of insulin units to be administered will continue to be high. Although this article primarily focuses on U500R, health care professionals should refer to each manufacturer’s resources to evaluate their respective concentrated insulin. Pharmacists can help to identify the appropriate patient for each concentrated insulin and manage prescribing and pharmacy systems to enable clear product selection by brand, dosing in units, and inclusion of reminders that aid in patient education. When a patient is being transitioned from one insulin to another, considerations for the right concentration include the insulin’s time-action profile, dosing schedule, delivery device, the right syringe or pen needle, management of hypoglycemia, and affordability, all of which are paramount to achieving glycemic control.

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12. Klonoff D, Nayberg I, Erbstein F, Cali A, Brulle-Wohlhueter C, Haak T. Usability of the Gla-300 Injection Device Compared With Three Other Commercialized Disposable Insulin Pens: Results of an Interview-Based Survey. J Diabetes Sci Technol. 2015;9(4):936-938. doi: 10.1177/1932296815586219. 13. Wang T, Conrad KA, van Brunt K, Rees TM. Attributes Influencing Insulin Pen Preference Among Caregivers and Patients With Diabetes Who Require Greater Than 20 Units of Mealtime Insulin. J Diabetes Sci Technol. 2016;10(4):923- 931. doi: 10.1177/1932296816633232.

14. FDA. Product-Specific Guidances for Generic Drug Development. www.fda. gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207. htm. Accessed June 25, 2018.

15. Meneghini L, Atkin SL, Gough SC, Raz I, Blonde L, Shestakova M, et al. The efficacy and safety of insulin degludec given in variable once-daily dosing intervals compared with insulin glargine and insulin degludec dosed at the same time daily: a 26-week, randomized, open-label, parallel-group, treat-to-target trial in individuals with type 2 diabetes. Diabetes Care. 2013;36(4):858-864. doi: 10.2337/dc12-1668.