Michael McShea, RPH

The number of concentrated insulin products available to treat patients with diabetes has expanded over the last several years in the United States (table ).

 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.

 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.

Findings from recent market research among pharmacists and other health care professionals identified a need for a deeper understanding of all concentrated insulins.

 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?

 and the American Association of Clinical Endocrinology

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.

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.

 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.

 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.

 The lower injection volume to deliver a dose can help reduce the pain associated with injecting higher doses of U-100 insulins.

 Surveyed patients generally preferred higher concentration insulin pens to U-100 insulin pens.

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.

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.”

 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.

 The insulin lispro U-200 pen offers double the pen-device capacity

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.

 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 glargine

 may need to be increased when transitioning from U-100 to U-300 and the TDD of U-500R

 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.

 U-500R provides 80% less injection volume than U-100 insulin

 and can be dosed as monotherapy with 2 or 3 injections per day due to its prandial-basal action.

WHAT ARE THE SAFETY CONCERNS WITH CONCENTRATED INSULIN?

As with all insulins, hypoglycemia is the primary safety concern with concentrated insulin therapy.

 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.

 and both formulations of insulin degludec

 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

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.

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.

 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.

 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.

 When administered subcutaneously 2 or 3 times each day, U-500R provides basal and mealtime coverage without the need for another insulin,

 unlike human regular insulin U-100 that provides only mealtime (or bolus) coverage.

 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?

The basal-bolus activity of U-500R is unique and attributed to its high concentration.

 Steady state is reached in 24 hours with twice-daily or thrice-daily subcutaneous administration.

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).

 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.

U-500R has a greater delay in peak effect, with a lower, more gradual decline in concentration, and prolonged duration of action. 

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,

 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).

 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.

 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. 

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.

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.

 For severe hypoglycemia, glucagon may be administered.

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.

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.

1. Humalog® U-100, U-200 [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2017. uspl.lilly.com/humalog/humalog.html#pi. Accessed June 25, 2018.

2. Tresiba® U-100, U-200 [prescribing information]. Plainsboro, NJ: Novo Nordisk; 2018. www.novo-pi.com/tresiba.pdf. Accessed June 25, 2018.

3. Toujeo® U-300 [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2018. products. sanofi.us/toujeo/toujeo.pdf. Accessed June 25, 2018.

4. Humulin® R U-500 [package insert]. Indianapolis, IN: Eli Lilly and Company; 2016. uspl.lilly.com/humulinru500/humulinru500.html#pi. Accessed June 25, 2018. 5. American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. No. 8. Diabetes Care.2018;41(suppl 1):S73-S85. doi: 10.2337/dc18-S008.

6. Eli Lilly and Company. U-500 Pharmacy Exploration Quantitative Report, 2017. Data on file.

7. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 2018 executive summary. 

. 2018;24(1):91-120. doi: 10.4158/CS-2017-0153.

8. Kabul S, Hood RC, Duan R, DeLozier AM, Settles J. Patient-reported outcomes in transition from high-dose U-100 insulin to human regular U-500 insulin in severely insulin-resistant patients with type 2 diabetes: analysis of a randomized clinical trial. 

. 2016;14(1):139. doi: 10.1186/s12955- 016-0541-4.

9. Gotzche D, Rasmussen BO, Pedersen MT, Sparre T, Bucher D, Niemeyer M. Injection force and dose accuracy of FlexTouch for the delivery of a new basal insulin. Expert 

. 2013;10(12):1613-1619. doi: 10.1517/17425247.2013.863276.

10. Rees TM, Lennartz AH, Ignaut DA. A comparison of glide force characteris-

tics between 2 prefilled insulin lispro pens. 

. 2015;9(2):316- 319. doi: 10.1177/1932296814567533.

11. Bohnet J, Schmitz M, Kamlot S, Abdel-Tawab M. Dosing accuracy and insulin flow rate characteristics of a new disposable insulin pen, FlexTouch, compared with SoloSTAR. J Diabetes Sci Technol. 2013;7(4):1021-1026.

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. 

. 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 

. 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. 

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Articles

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

Pharmacists need to be experts on follow-on biologics (FOBs), including biosimilars, so they can provide education to health professionals about safe prescribing

and use, which ultimately affects patient care. Seamless interchangeability among biosimilars and FOBs may not be permissible under the law, or as appropriate, as it is with brand and generic chemically derived drugs.

Several biologic patents expire in the next few years, and other manufacturers will offer alternatives with reduced costs. Health care practitioners will encounter many questions as biosimilars and FOBs enter the market. Many prescribers may not fully understand the differences between a biosimilar and the reference licensed biologic product.

Experts anticipate a 20% to 30% price reduction on biosimilars compared with the reference biologic, a price drop that would be necessary to create a viable biosimilar market through increased patient access.

 Payers anticipate biosimilars, and FOBs will be part of a strategy to reduce drug prices.

Depending on market dynamics and the competitive landscape, price reductions may come directly from the list price, rebates, or a combination of both. Some believe this represents a compelling business opportunity.

 Meanwhile, patients and providers face a challenge understanding immunogenicity, interchangeability, and pharmacy substitutions related to biosimilars.

Differing biologic formulations may pose concerns for efficacy and safety due to changes in manufacturing processes, protocols, packaging, and cold storage delivery.

 Keeping this in mind, pharmacists will be important contributors to the biosimilar and FOB information cascade shared with prescribers and patients as they make product decision choices.

There are important differences between biologics and biosimilars compared with chemically derived small molecules and their generics. First, biologics are produced in living cells or organisms and may comprise any virus, therapeutic serum, toxin, antitoxin, or analogous product, including therapeutic proteins that are not chemically synthesized polypeptides.

 These biologic products are typically used in the prevention, treatment, or cure of a disease. The first biologic product approved as a “drug” in 1982 was Humulin R (recombinant human insulin) from Eli Lilly and Company.10 Today, biopharmaceuticals include vaccines, blood products, allergenic extracts, human cells and tissues, gene therapies, and more.

Second, biologics differ from chemical drugs because they are larger, more complex molecules manufactured from living cells or organisms, susceptible to instability from external conditions, and associated with immunologic properties.

 A biosimilar is highly similar to an already approved licensed biologic molecule in which the manufacturing process details are proprietary information. This is the reason why manufacturers of a proposed biosimilar must develop an entirely new process that can lead to small differences in structure, stability, impurities, and excipients compared with the reference biologic.

 Approval processes require that these changes have no clinically meaningful significance. Therefore, biosimilars are similar to the reference biologic, not identical, so they are not generically equivalent.

Different terminology describes biosimilars and FOBs, and it is important for pharmacists to understand how the terms relate to federal and state regulations. In the United States, biosimilars are approved under Section 351 of the Public Health Service Act (PHS Act). Interchangeability is an FDA regulatory designation that the manufacturer requests, suggesting that a biosimilar draft a higher level of regulation than biosimilarity. However, specific FDA guidance on interchangeability has not yet been finalized. At least 35 states have passed legislation regarding the rules for biosimilar substitution (ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution- of-biosimilars.aspx). Therefore, substitution occurs at the pharmacy and is regulated by state legislatures.

States may define the practice of substitution so that the pharmacist is able to substitute an FDA-licensed interchangeable biosimilar for a referenced biologic or vice versa without direct prescriber consult based on state-specific regulations.

 Interchangeability refers to a decision by a regulatory authority, based on scientific data submitted by the manufacturer, that the biosimilar product is appropriate for substitution for the reference biological product under local laws and pharmacy practices.

Switching occurs when the prescriber chooses to change a patient’s therapy from a registered licensed biologic to a biosimilar product, or vice versa.

 Additional terms of importance include “not similar,” “similar,” “highly similar,” and “highly similar with fingerprint-like similarity.” These categories described by the FDA further quantify the degree of similarity between 2 products.

 In the United States, some follow-on biologics may be similar versions of already approved listed drugs upon which the new drug application (NDA) is filed under section 505(b)(2) of the Food, Drug, and Cosmetic Act. Biologics filed through the 505(b)(2) pathway are also obligated to meet safety and efficacy requirements as defined by the FDA.

 Biosimilars and FOBs are not generics; therefore, they are not “bioequivalent” to the listed drug relied upon. For biologics, 2 products manufactured by different companies (without technology transfer) cannot be said to contain the identical active ingredient or to be bioequivalent.

Biosimilar regulations continue to evolve, but pharmacists should be familiar with some regulatory pathways currently in place. The 351(k) pathway is an abbreviated pathway for licensing of products shown to be biosimilar to an FDA-approved reference product.

 Zarxio (filgrastim-sndz), the first approved biosimilar in the United States, went through this pathway.

 The totality-of-evidence approach is used to demonstrate biosimilarity and requires structural and functional characterization, nonclinical evaluation, human pharmacokinetics (PK) and pharmacodynamics (PD) data, clinical immunogenicity data, and comparative clinical study data. Clinically meaningful differences could include a difference in the expected range of safety, purity, or potency of the proposed product and the reference product. In contrast, slight differences in rates of occurrence of certain adverse events (AEs) between the 2 products ordinarily would not be considered a clinically meaningful difference.

Alternatively, the 505(b)(2) pathway is used in cases where the listed drug relied upon made its application under section 505. These submissions require an NDA and have been used by insulins, calcitonin, and human growth hormone.

 In 2010, the Affordable Care Act (ACA) required all biologics and biosimilars to file a biologics license application (BLA) and previously approved products to be subject to a transition period until 2020. Between now and 2020, similar biologics will either be filed under the 351(k) pathway or the 505(b)(2) pathway pending transition to a biologics or biosimilar designation on March 23, 2020.

 Basaglar (insulin glargine injection) was recently approved and filed through the 505(b)(2) pathway.

Since the introduction of biologic licensing under the PHS Act, the FDA introduced a new resource, 

. This resource provides lists of licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. Besides providing key dates and lists of reference products, a portion of 

 assigns 1 of 2 grades to biologics, biosimilar (B) or interchangeable (I) to the reference product. Interchangeable would require additional data for approval compared with a biosimilar designation.

 This resource is meant to closely model 

, which describes the therapeutic equivalence and safety between 2 related drug products.

 will add all new biologic products approved through the 351(k) pathway, with the first entry being Zarxio (filgrastim-sndz).

 Biopharmaceuticals submitted for approval through the 505(b)(2) pathway are not yet reflected in 

. However, as of March 23, 2020, these products will be transitioned to obtain their BLA previously mentioned under 351 and, hence, they will be defined in the resource.

Meanwhile, pharmacists will have to pay close attention to regulations around biologic products.

Within the 351(k) pathway, there are still many questions regarding biosimilar naming and labeling in the United States. The FDA has asked for input on draft guidances on biosimilar naming and labeling.

 On August 28, 2015, the FDA announced the availability of a draft guidance, entitled “Nonproprietary Naming of Biological Products.” The draft guidance describes current thinking on the need for biologic products licensed under the PHS Act to bear a nonproprietary name that includes an FDA-designated suffix.

 This guidance has been applied to Zarxio (filgrastim-sndz), the first biosimilar approved in March 2015.

 Inflectra (infliximab-dyyb) is the second example of an approved biosimilar in the United States.

An approach to streamline naming could be to decide that the nonproprietary names are similar, but not the same. Utilizing the same nonproprietary name could imply the product is identical and approved for all of the same indications, whereas the biosimilar could be approved only for a subset of the reference biologic’s indications.

Therefore, each product would hold its own brand name to further help to prevent confusion on which product should be dispensed.

Prescribers and pharmacists need to prepare for the adoption of biosimilars in practice to support their patients appropriately. As previously mentioned, biosimilars are not interchangeable unless specifically requested by the manufacturer and approved by the FDA under the higher regulatory standard of interchangeability.

If a regulatory authority determines the biosimilar to be interchangeable, this would allow for direct substitution. Pharmacists will then have to know which products can be directly substituted and those that would require prescriber consultation. Additionally, pharmacists must follow individual state regulations. Prescribers will want accurate documentation of which biosimilar their patient is utilizing.

 Although complicated, this provides an opportunity for pharmacists to be a valued source of education to prescribing health care professionals. Pharmacists can be the local biosimilar experts and implement sound pharmacovigilance practices, as well as have the knowledge of niche therapeutic options and potential cost advantages for patients, prescribers, and health care systems.

Basaglar (insulin glargine injection) was recently approved through a 505(b)(2)) submission with no differentiation in the non-proprietary name associated with Lantus (Sanofi; Paris, France). Biologics manufactured by different companies (without technology transfer) are not identical despite having the same primary amino acid structure or being bioequivalent.

 The 2 molecules are not considered bioequivalent, resulting in 2 products that are not automatically substitutable unless listed as such in 

. Prescribers maintain the option to transition patients from one product to the other as a matter of choice, but should do so when prescribing by brand name to enable management of potential clinical and safety issues that may occur. Somatropin, a growth hormone, marketed under several brand names, has the same nonproprietary name resulting in similar challenges.

If biosimilars and FOBs are not prescribed by their brand name, pharmacists and prescribers should be aware of the potential confusion that may be generated by electronic medical records, e-prescribing, prescription dispensing practices, AE reporting, and patient discussions. When a prescription is written for the nonproprietary name, pharmacists should verify with the prescriber of the intended brand. To further complicate matters, Merck and Mylan are anticipated to seek approval of their versions of insulin glargine sometime in the near future.

There are a number of factors that can influence the development of an immune response from a biologic or biosimilar, and they can be product-, patient-, or treatment-related.

 The body has the ability to detect foreign proteins and produce (neutralizing) antibodies. Therefore, the immunologic profile of a biosimilar or an FOB should be more important than cost considerations when determining their place in therapy.

Payers may desire interchangeable biologic products analogous to AB-rated bioequivalent generics, but product complexity complicates this circumstance. Small changes in the manufacturing process or product excipients may impact the PD and PK, efficacy, structure, stability, impurities, immunogenicity, and AEs associated with the biotherapeutic.

 One must remember that biologics are inherently immunogenic. An example of this was Coagulation Factor VIII. This biotherapeutic clearly showed a link between the manufacturing process and the product profile. A degradation product of factor VIII led to increased immunogenicity.

Despite issues pertaining to complexity and risk, biosimilar or FOB agents can safely be produced using different manufacturing processes and protocols. Health care professionals facilitating patient care should be properly educated on the background of biotechnological manufacturing and how these processes can differ between manufacturers.

BIOSIMILARS AND FOLLOW-ON BIOLOGICS IN PRACTICE SITES

Pharmacists need to prepare for the introduction of biosimilars and FOBs for use in both the institutional and outpatient settings. Starting with hospital formularies, the adoption of these products will have different challenges to overcome compared with chemical drugs. This will continue into the outpatient setting, where payer formularies and product availability may differ from the prescribing institution. The more complex adoption into a health-system formulary may require clarity of past manufacturing issues, supply chain availability, patient monitoring, and increased provider and patient education. The institutional setting may need to invest resources into evaluating and monitoring the use of the reference product over that of a single, or even multiple, FOB products.

As the medication expert, pharmacists have the opportunity to offer guidance in all stages and areas of biologic use. This is especially true as collaborative practice agreements and pharmacist credentialing and certifications continue to develop. Prescribers will need to appreciate how better access to biotherapeutics may impact patient adherence to treatment regimens and begin taking steps now to address these potential issues.

 Patient adherence may also be affected by device ease of use, patient support programs, and product affordability.

 Patient perceptions of biosimilar and FOB therapeutics will be a barrier if the patient perceives these alternatives as inferior to the reference product. If they are providing meaningful patient education, pharmacists must be knowledgeable about a biotherapeutic’s efficacy, immunogenicity, and AEs that may be uncommon compared with the listed drug relied upon.

 Postmarketing surveillance also is critical to confirm the regulatory decision of biosimilarity, and it is important for the pharmacist to report AEs in conjunction with the prescriber’s responsibility.

As previously stated, experts anticipate that a 20% to 30% price reduction from the reference biologic would create a viable biosimilar and FOB market through increased patient access. This has the potential to impact what a patient pays out-of-pocket (OOP). Reductions in list price will impact patients in benefit design, such as high-deductible plans and co-insurance, where OOP costs are determined by a percentage of a medication’s list price instead of a fixed co-pay. For example, a patient who is in a high-deductible plan will pay 100% of the list price for each prescription until they reach their OOP benefit maximum, which can be as high as $6500 for a single plan and $13,000 for a family plan, as mandated by the ACA. For a patient with coinsurance, their OOP may be 10% or 20% of the list price. Therefore, the introduction of biosimilars and FOBs may impact the patient’s cost, whereby if the biosimilar list price or the FOB price is lower than the reference product, the patient’s OOP costs will be lower.

In benefit designs where patient OOP is a fixed co-pay, price concessions from manufacturers may not impact a patient’s OOP expenses. Considering all the factors discussed, pharmacists have the opportunity to proactively direct patients and prescribers to the lower-priced biologic.

Biopharmaceuticals offer management options and solutions for a vast number of conditions and diseases. Ultimately, they help improve patient lives. Increasing availability of biosimilars and FOBs should increase prescriber choice of, and patient access to, biotherapeutics. Improving prescriber confidence in biosimilars and FOBs will help to overcome negative patient perceptions that may mirror what generics faced when initially compared with brand thereapeutics.

 Prescriber education on immunogenicity profiles and clarity on product names and documentation will demand interprofessional communication in the process. Payers may dictate access to different products, and it will be up to the health care team to be knowledgeable of available options. Products may not be interchangeable based on approval status, so the pharmacist has a responsibility to ensure the accuracy and appropriateness of their patient’s regimen. If pharmacists understand the regulations and biosimilar/FOB marketplace, they will be able to offer pertinent recommendations to prescribers and meaningful consultation to patients.

Michael McShea, RPh, graduated from the University of South Carolina, College of Pharmacy with his BS in Pharmacy. His experiences span marketing, account management, hospital and retail pharmacy, long term care, and diabetes and hospital account sales. He joined Eli Lilly & Co. in 1989 and is currently in Channel Strategy focusing on the Endocrine platform. His responsibilities include identifying and understanding the environment and capabilities in various traditional Trade and emerging Specialty Channels, including distribution and pharmacy, as well as the evolving capabilities of the organizations and vendor partners actively participating in those channels. He is also currently a member of the advisory panel for Specialty Pharmacy Times and Pharmacy Times. He places importance on connecting patients with product within the pharmacy channel to ultimately enhance patient experiences and care in support of improved patient outcomes.

Mark Borns, PharmD, graduated from The Ohio State University in 2016 with his Doctorate of Pharmacy and also has a BS in Pharmaceutical Sciences. He is currently a Visiting Scientist Fellow at Eli Lilly and Company in Indianapolis, Indiana, focused in Global Pricing, Reimbursement and Access. He is devoted to the value of biopharmaceutical innovation and the importance of patient access to medications.

Roy Daniel Pollom, MD, received his MD from Indiana University School of Medicine in 1977 and completed his residency in Internal Medicine in 1980. For the last 15 years, Dr. Pollom worked at Diabetes, Internal Medicine & Endocrinology, a multi-physician group practice at Community Health Network in Indianapolis, Indiana, specializing in the care of children and adults with diabetes. Additionally, he served as Medical Director at the Indiana Heart Hospital providing leadership in the management of diabetes and hyperglycemia in hospitalized patients with cardiovascular disease. His work with cardiovascular and peripheral vascular surgeons helped to establish evidence-based glycemic guidelines to improved outcomes in surgical patients. He joined Eli Lilly & Co. as a Sr. Medical Advisor in 2013 after more than 30 years of treating people with diabetes in private practice. His areas of expertise include type 1 and type 2 diabetes management, diabetes in pregnancy, continuous insulin pump and glucose sensor technology, stress hyperglycemia management during hospitalization and electronic glucose data analysis.

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Pharmacists must be experts on follow-on biologics (FOBs), including biosimilars, so they can provide education to health professionals about safe prescribing
and use, which ultimately affects patient care.

Biosimilars and Follow-on Biologics

Pharmacists need to be experts on follow-on biologics (FOBs), including biosimilars, so they can provide education to health professionals about safe prescribing and use, which ultimately affects patient care. Seamless interchangeability among biosimilars and FOBs may not be permissible under the law, or as appropriate, as it is with brand and generic chemically-derived drugs.

Pharmacists need to be experts on follow-on biologics, including biosimilars, so they can provide education to health professionals about safe prescribing and use.