The Nuances Surrounding Insulin Prescribing

Abstract

Knowledge of and expertise in insulin prescribing is crucial for health care providers who care for people with diabetes. This article reviews the available insulin preparations, how they are packaged, and nuances related to storage and use that inform the prescribing of this life-saving medication for patients. Insulin prescribing that is done correctly will save time and reduce problematic errors that could put patients at risk.

Approximately 34 million people in the United States (10.5% of the population) have diagnosed or undiagnosed diabetes (1). Insulin is an absolute requirement for people with type 1 diabetes and is necessary for glucose control for up to one-third of those with type 2 diabetes. Throughout the past century, the initial prototype insulin product has undergone multiple improvements with regard to purity, extended duration with the addition of protamine, and, more recently, recombinant technology that has allowed the development of insulin analogs with different pharmacokinetic properties (2). These advances have resulted in a plethora of new insulin formulations and have been accompanied by technological advances including the development of disposable insulin pens with fine needles, insulin pumps, and digital connected, or “smart” insulin pens. A recent categorical change of insulin from a drug to a biologic by the U.S. Food and Drug Administration (FDA) will foster an increase in available biosimilar insulin products that will add options, but also complexity, for health care providers (HCPs) (3).

This article discusses the currently available insulin products, including different formulations and concentrations of insulin as well as available delivery devices. Its goal is to assist HCPs in better understanding the nuances of insulin prescribing, which in turn will improve care for people who either use insulin injections or continuous subcutaneous insulin infusion (insulin pump therapy). Knowledge of the many formulations of insulin and their delivery devices will allow insulin prescribers to match their patients’ needs with the most appropriate type of insulin and the most appropriate delivery method, while reducing prescribing errors.

Diabetes HCPs should be able to accurately prescribe insulin to individuals with differing insulin requirements, from those requiring very low doses to those needing hundreds of units of insulin per day. People with type 2 diabetes and moderate hyperglycemia on noninsulin therapies may require only long-acting insulin, whereas those with type 1 diabetes, severe type 3c diabetes, or type 2 diabetes not well managed with basal insulin alone will require more complex regimens for physiologic insulin replacement. Patients who use a multiple daily injection (MDI) insulin regimen require both long-acting and rapid-acting insulins, generally delivered by either pen devices or insulin pumps. Most are taught to adjust their insulin doses, and variations in total daily dose (TDD) requirements are common.

The American Diabetes Association recommends that people with type 1 diabetes or those with type 2 diabetes on MDI therapy consider using an insulin pump with automated insulin delivery (AID) functionality to improve overall glucose control and reduce hypoglycemia (4). As these modern pumps and other insulin delivery devices become the standard of care, all diabetes HCPs will need to know how to manage the care of people who use them, including how to appropriately prescribe insulin, which is the focus of this review.

Insulin Preparations and Packaging

Insulin is packaged in various ways that can be broadly classified as vials, prefilled pens, and cartridges and allow insulin to be administered via different modalities (Supplementary Table S1). Vials of insulin are available for long-, intermediate-, short-, rapid-, and ultra-rapid-acting insulins, as well as premixed insulin products and the concentrated U-500 (500 units/mL) regular insulin formulation. Paying attention to the various sizes of vials and to the concentration of the insulin prescribed is important because these factors determine the number of units of insulin available per prescription. The most common type of insulin vials contain 10 mL and can be prescribed for all of the available insulins except for some long- acting products, including glargine-aglr, glargine U-300 (300 units/mL), and the glargine biosimilar Basaglar, which are only available in pen devices. For patients requiring very low doses of insulin, 3-mL vials are available for the rapid-acting lispro biosimilar Admelog, short-acting regular insulin, intermediate-acting NPH insulin, and the premixed 70/30 isophane/regular insulin combination (5–7). The difference between a 10-mL and a 3-mL vial is important. For example, if the insulin concentration is 100 units/mL (U-100), then a 10-mL vial will contain 1,000 units of insulin compared with 300 units in a 3-mL vial. U-500 regular insulin, which is ultra-concentrated, is uniquely available in a 20-mL vial, which holds 10,000 units and should be used with a dedicated U-500 insulin syringe (8). Using insulin from vials requires that it be drawn up with a syringe before it can be injected or added to a pump cartridge or reservoir. Patients need adequate vision and dexterity to manage this process and sufficient training to avoid errors. For these reasons, and for more accurate dosing, most insulins are now available in prefilled pens.

Prefilled insulin pens are available for every type of insulin, including long-, intermediate-, short-, rapid-, and ultra-rapid-acting formulations, as well as premixed insulin, and U-200 (200 units/mL), U-300, and U-500 insulin formulations. Insulin pens typically contain 3 mL of insulin, which equates to 300 units of insulin per pen, assuming the insulin concentration is 100 units/mL. Insulin lispro and lispro-aabc are also available in a concentrated U-200 formulation, which increases the 3-mL pen capacity to a total of 600 units (9,10). Similarly, U-200 insulin degludec is available in a 3-mL pen containing a total of 600 units. U-500 regular insulin is the most concentrated insulin available in a prefilled pen, with each pen containing 1,500 units of insulin (8).

The long-acting insulins are generally available in concentrations of 100 units/mL with two exceptions: glargine U-300 and degludec U-200 (11,12). The standard U-100 pens deliver insulin in 1-unit increments to a maximum bolus of 60–80 units. Lispro and lispro-aabc are also available in U-100 pens that deliver doses in 0.5-unit increments up to a 30-unit maximum bolus (9,10). U-200 lispro and lispro-aabc insulin pens deliver insulin in 1-unit increments up to 60 units. Degludec U-200 pens deliver insulin in 2-unit increments. Glargine U-300 is available in 1.5- or 3-mL pens that hold 450 and 900 units, respectively (11). Glargine U-300 also comes in a pen that delivers 1-unit increments up to an 80-unit maximum bolus and another pen that delivers 2-unit increments up to a 160-unit maximum single dose (11). The U-500 regular insulin pen delivers insulin in 5-unit increments to a 300-unit maximum dose for highly insulin-resistant patients (8).

When prescribing insulin to be delivered by either pens or vials and syringes, HCPs must account for the 2 units of insulin required to prime a pen before each dose to eliminate air bubbles that can lead to erroneous dosing. Priming (sometimes called “air shots”) can add 6–8 units/day to a patient’s TDD with U-100 insulins and even more with concentrated insulins. The prescription should reflect this added requirement.

A sample prescription might provide these directions: “Take up to 10 units before meals, up to 6 units for snacks, plus 8 units for priming of the pen (or syringe), for a total daily dose of up to 44 units.” A 30-day supply of insulin increases from 900 units (three pens or one vial per month for the dose typically administered) to 1,320 units (five pens per month or five vials for 3 months) when the additional factors are considered. When prescribing insulin pens, the quantity of insulin to be dispensed can be ordered in milliliters (e.g., “15 mL” will provide a box of five pens of most insulins).

The two newer formulations of ultra-rapid-acting insulin aspart and lispro-aabc retain the same structure as their rapid-acting analogs but have altered excipients for faster absorption (9,13). This change allows both insulins to be used before meals or within 20 minutes after the start of meals, which can be helpful for people who are unable to take prandial doses several minutes before their meals. Insulin cartridges of rapid- and ultra-rapid-acting insulins are available for lispro, lispro-aabc, aspart, and faster-acting aspart insulins. These 3-mL cartridges contain 300 units of insulin and are sold in packs of five for use in reusable pens and smart insulin pens.

The choice of pens versus vials should be based on patient characteristics and shared decision-making. Vials and syringes are less expensive and may be appropriate for people taking moderate to larger doses of insulin. Insulin pens provide more accurate dosing, particularly at low doses. Note that people with vision impairment can often self-manage their diabetes with insulin pens by listening and sensing the number of clicks, which represent the number of units that will be taken. Prescribers should watch patients with tremor or other dexterity problems administer insulin to ensure that they are able to manage the prescribed pen device. Some pens require users to forcefully push a thumb screw or dose knob, whereas others use a push button mechanism with low injection force needed per dose.

The most rapidly acting of all insulin products is the ultra-rapid-acting inhaled insulin Afrezza, which is human insulin powder absorbed to technosphere particles to allow for alveolar absorption (14). The insulin is available in 4-, 8-, and 12-unit single-use cartridges that are placed in a small inhaler device. To achieve the right dose, one or more cartridges (necessitating one or more inhalations) can be administered per meal. Packaging includes three cartridges per blister strip, which are placed on a card with 15 total cartridges per card. Afrezza is available in packages containing 90–180 cartridges with varying cartridge doses and two inhalers per pack. The inhaler device should be replaced every 15 days. Opened cartridges within opened strips must be stored at room temperature and used within 3 days. Afrezza has the advantage of avoiding injections while offering the most rapid absorption and peak of all of the available insulins.

Smart Insulin Pens

Two smart insulin pens—NovoPen Echo and InPen— are available in the United States (15,16). The NovoPen Echo is a reusable pen compatible with aspart U-100 cartridges with a 300-unit capacity and delivers insulin in 0.5-unit increments to a 30-unit maximum bolus. This pen is capable of storing data on the timing and amount of insulin administered for later download (15). The InPen is a smart insulin pen compatible with lispro, lispro-aabc, aspart, and faster aspart insulins. It has the same maximum and bolus increments as other reusable U-100 pens. Through an app on a compatible Android or iOS smartphone, individuals are able to dose insulin based on programmed settings, including options for variable meal sizes, fixed meal dosing, or carbohydrate ratios via a dose calculator. The InPen also allows for connectivity with Medtronic and Dexcom continuous glucose monitoring systems and provides dosing reminders for long-acting insulin (16). Smart pens are appropriate for patients who need assistance with dosing calculations and those who could benefit from greater communication with support people and HCPs through the app’s upload features.

Special Populations

Children Needing Low Doses

Small children who are insulin sensitive, despite dosing in 0.5-unit increments of U-100 insulin, may still experience hypoglycemia. Conversely, efforts to avoid hypoglycemia can lead to inadequate treatment and poor glycemic control. To address this problem, sterile insulin diluents are available from Eli Lilly and Novo Nordisk that can be prescribed to create insulin concentrations lower than 100 units/mL. However, there are many barriers to diluting insulin. Not all pharmacies perform the dilution, and patients who are exposed to higher concentrations of excipients may encounter health risks. Adding insulin dilution to the regimen places additional stress on parents struggling to manage a baby or small child with diabetes and may increase the risk of errors (17). Parents can also use pens that deliver insulin in 0.5-unit increments; however, only U-100 lispro and lispro-aabc are available in pens with 0.5-unit dosing, and this option is not available at all for long-acting insulins.

Individuals Who Require High Doses

Concentrated insulins are useful for patients who require higher doses and are available in both long-acting (glargine U-300 and degludec U-200) and rapid-acting (lispro U-200 and lispro aabc U-200) formulations (18). Note that some of the pen devices provide dosing in 2-unit increments only, so instructions for both dosing and titration must be given in 2-unit increments for patients who use carbohydrate counting or a correction factor. U-500 regular insulin is appropriate for people who need >200 units of insulin per day and can be administered in 5-unit increments given in either two or three doses per day (8).

Individuals Using Insulin During Pregnancy

Insulin use is necessary during pregnancy for people with preexisting type 1 or type 2 diabetes and some people with gestational diabetes. The previously used grading system for drug safety in pregnancy has been replaced by the inclusion of both animal and human study results in the prescribing information. Prescribers can make informed decisions about maternal and fetal risks based on this information. Note that previously designated Category B insulins (i.e., those posing no demonstrable risk to a fetus in animal studies and with no well-controlled studies in pregnant women) include regular insulin U-100 and U-500, aspart, lispro U-100 and U-200, NPH insulin, and insulin detemir. Studies in pregnant women have been conducted for degludec U-100 and U-200, with updated information available in the package inserts (19). Glargine U-100 and U-300 insulins have also been studied in pregnancy and do not show increased risk (20). Given the importance of glucose control during pregnancy, prescribing information and package inserts should be consulted for updated information about the use of specific products in pregnancy, which may change over time.

Insulin Prescribing for Insulin Pumps

There are three main insulin pump manufacturers, including Tandem, Insulet, and Medtronic. Additionally, patch pumps, including the V-Go made by Mannkind and the CeQur Simplicity made by CeQur Corporation, are available (Supplementary Table S2). Each pump has a cartridge or reservoir that holds a discrete number of units of insulin with a minimum fill requirement and a maximum capacity. For instance, the Tandem and Medtronic pump reservoirs can hold up to 300 units of insulin in the reservoir, whereas the Omnipod tubeless pump has capacity for 200 units. Patients may elect not to fill the cartridge or reservoir to capacity depending on their daily insulin requirement. Some pump data downloads show patients’ TDD, the amount of insulin instilled, and the number of days before a set change. A patient who has a 50-unit TDD will need a prescription for 20 mL per month rather than 15 mL per month because of the added insulin required for the reservoir.

Another differentiating and important pump feature is the amount of insulin necessary to prime the tubing and fill the cannula. It is important to account for this amount when prescribing insulin vials for patients using pump therapy. For the Tandem pumps, depending on the length of tubing, 15–30 units of insulin is needed for priming, and another ∼1 unit is needed for the cannula to fill. This is in contrast to the Omnipod pumps, which only require up to 5 units for priming and <1 unit for cannula fill because they are tubeless.

When prescribing insulin for patients who use a pump, HCPs must account for not only patients’ TDD, but also the amount of insulin lost in the tubing with each infusion set change and additional insulin needed to either meet the pump’s minimum requirements or for high-side dosing (>1 unit/kg/day) to ensure that patients will have an adequate supply for 30 days. This amount is variable based on pump and its tubing length and can range from 10 to 20 units. For example, a patient whose TDD is 30 units will require about 125 units every 3 days for a tubed pump, or 1,250 units per month. If the prescriber writes a prescription for only one vial per month, the patient will not have a sufficient amount of insulin to meet these needs. Furthermore, if this same patient encounters a site problem and needs to refill a reservoir and tubing unexpectedly, he or she will likely need closer to 1,500 units per month.

Several rapid-acting insulins are approved for use in insulin pumps, including lispro and its biosimilar (Admelog) and aspart. Glulisine is approved for use in Omnipod tubeless pumps; however, it may not be ideal for systems with tubing given findings of higher rates of pump or tubing occlusion with glulisine (17,21). Medtronic MiniMed and Tandem t:slim pumps are only approved to use with lispro and aspart U-100 insulin. It should be noted that the ultra-rapid-acting insulins faster aspart and lispro-aabc are FDA-approved for use in insulin pumps; however, there are nuances to these approvals. In the onset 5 trial, which tested faster aspart, older Medtronic pumps, including the MiniMed 530G, Paradigm Veo, Paradigm Revel, and Paradigm were used (22). In the PRONTO-PUMP-2 study evaluating lispro-aabc, the MiniMed 530G, Paradigm Revel, MiniMed 630G, and Paradigm Veo pumps were used (23). Thus, caution should be used when extrapolating results of these trials to other insulin pumps. Without dedicated testing, it is unclear whether the ultra-rapid-acting insulins will be handled by AID pumps automated delivery algorithms in the same manner as rapid-acting analog insulins. According to Insulet, its Omnipod DASH pump is compatible with any of the rapid- and ultra-rapid-acting insulins for up to 3 days and with glulisine for up to 2 days (24). The Omnipod 5 AID pump is approved for use with lispro and its biosimilar Admelog, as well as aspart (25).

From a prescribing perspective, it is also worth noting that insulin pumps are covered under Medicare Part B, and insulin used in the pumps is also covered under Medicare Part B as opposed to Part D, which covers all other insulin prescriptions (26,27). It is necessary to specify on the insulin prescription, “For use in insulin pump” to use the Part B pricing option. Using this option may keep patients out of the coverage gap, or so-called “donut hole,” which only applies to medications billed under Part D.

Patients must be careful about insulin degradation when it is exposed to high temperatures, and it is recommended that insulin in the pump reservoir be disposed of when exposed to temperatures exceeding the recommended limit. For extended periods in the heat, patients have used cool packs around their pump to prevent insulin degradation.

Insulin Administration

Insulin that is administered subcutaneously with insulin syringes or insulin pens or through infusion sets connected to an insulin pump share some of the same potential problems. Instructing patients on the art of injecting insulin is crucial to avoid a gamut of possibilities, including total lack of absorption; repetitive injection into the same site, leading to lipohypertrophy; or injection into muscle, leading to too-rapid absorption. Certain areas of the body absorb insulin more quickly than others. The difference is proportional to the average thickness of the skin that must be penetrated to reach the subcutaneous layer (28). The following body areas are ordered from most rapid to least rapid insulin absorption: abdomen, back of arms, thighs, and buttocks (28). Site rotation is a crucial step to avoid lipohypertrophy. In one study, 21% of individuals who administered two to five injections per day used the same injection site for the entire day or even for a few days, a practice that may result in lipohypertrophy or other skin changes (29).

Insulin syringes are plastic and disposable and are available with various needle gauges and lengths. Insulin syringes come in different sizes, including 0.3-, 0.5-, and 1.0-mL sizes that hold up to 30, 50, and 100 units of insulin, respectively. Needle gauges are 28–31, with 31 being the finest gauge. Needle lengths are typically 5, 6, 8, and 12.7 mm (3/16, 5/16, 8/16, and 1/2 inch, respectively). Similarly, pen needles have various lengths and gauges, including lengths of 4, 5, 6, 8, and 12.7 mm and gauges from 29 to 32. The thickness of the needle, known as the gauge, is important in that the higher the gauge is, the thinner the needle will be. The thinnest available pen needle is 32 gauge, and the thinnest insulin syringe needle is 31 gauge. Although thinner needles are more comfortable for patients, they also have a tendency to bend more easily (30).

Based on guidance from the 2015 Forum for Injection Technique and Therapy: Expert Recommendations (FITTER) workshop, a 4-mm needle is considered the safest pen needle for adults and children regardless of age, sex, ethnicity, or BMI (31). In patients with obesity, a 4-mm needle can still be used effectively and safely, although a 5-mm needle is also acceptable (31). Longer needles are generally not needed for insulin injection, but they might make it easier to withdraw insulin from a vial. Insulin syringes or pens should be held at a 90° angle for most individuals or injected into a skinfold at <90°. A 45° angle may be used for individuals who are unable to lift a skinfold and are using a 6-mm needle (28,31).

When prescribing pen needles, it is helpful to know that pharmacies package them in boxes in quantities of 50 or 100. Insulin syringes are supplied in packages of 10 or boxes of 100. At a minimum, insulin pump users need to have a supply of insulin syringes on hand for pump failure situations. Infusion sets deliver insulin from the pump to the subcutaneous space via tubing and cannula. Infusion sets are broadly divided as either angled (inserted at a 30° angle) or straight (inserted at a 90° angle). Site rotation every 2–3 days has been the standard wear-time (32). Medtronic pumps now offer a 7-day infusion set.

Additionally, NPH or premixed insulins (70/30 isophane and short-acting regular insulin, 75/25 insulin lispro protamine and insulin lispro, and 70/30 insulin aspart protamine and insulin aspart) require suspension of the insulin by rolling and turning the vial or pen prior to injection. In one study, 35% of individuals did not resuspend their insulin as recommended (29).

Insulin Stability and Storage

It is imperative that patients are educated on the importance of recommended storage conditions for insulin and the duration of use after opening to ensure insulin potency. In general, unopened insulin should be refrigerated but never placed in the freezer. Once insulin is opened, it can be stored at room temperature (<86°F [30°C]) for a defined time range between 10 and 56 days, depending on the specific product (Supplementary Table S1) (5,8,10,12–14,33). For glulisine, the manufacturer recommends storing vials away from light and at a lower temperature threshold of <77°F (25°C) once opened (34). Furthermore, when used in an insulin pump, the reservoir or cartridge of glulisine should be changed every 48 hours (34).

Storage of insulin pens after opening varies from 10 to 56 days only at room temperature except for degludec pens, which can be stored at room temperature or refrigerated (16). Afrezza is available in packages containing 90–180 cartridges, with varying cartridge doses and two inhalers per pack. Opened blister strips must be stored in room temperature and used in 3 days (14).

When hyperglycemia occurs unexpectedly and is not corrected with usual measures, loss of insulin potency should be suspected (35). If this happens after a new vial or box of pens is opened, the problem may have occurred during shipping or storage at the pharmacy, typically as a result of adverse temperature excursions. If hyperglycemia becomes problematic at the end of a vial, contamination with air or storage for too long at room temperature could be the culprit (35). Hyperglycemia is common among insulin pump users who spend time outside in hot or cold temperatures. Changing the insulin in the pump reservoir or opening a new vial or pen may be needed to reestablish glucose control.

Pharmacy Issues

When calculating how much insulin a patient requires each month, HCPs must take into account the patient’s maximum daily insulin requirements, including what will be needed for patients who use carbohydrate counting and a correction scale to determine bolus doses. According to the Centers for Medicare & Medicaid Services, when calculating day supply (i.e., how many days a prescription will cover) of insulin, one first needs to calculate the total number of units to be dispensed by multiplying the number of units/mL (e.g., 100 units/mL) by the number of millimeters to be dispensed (e.g., a 3-mL pen). Then divide the total number of units to be dispensed (e.g., 300 units) by the total units prescribed per day (e.g., 10 units). In this example, a total of 300 units will be dispensed for a 30-day supply (36). Prescribers should consider small, 3-mL vials or pens for patients who use low doses of insulin. When determining day supply, prescribers also need to take into account the expiration date of the vial or pen after it is opened. For example, insulin lispro is only stable for 28 days at room temperature; thus, the maximum day supply should be 28 days. Prescribers may need to add notes to the pharmacy for insulin quantities that do not match the day supply limit.

The day supply limit is the number of days the prescription is written to cover plus the extra days of insulin supplied because of the fixed amount of insulin in vials and pens. Rounding to the next available vial and/or pen size to meet the required day supply has caused issues for pharmacies through the years. To meet the day supply limit covered by insurance companies and pharmacist benefit managers, it was common practice for pharmacy personnel to split pen boxes and dispense pens outside of their original cartons. The concern with this practice is that the insulin pens are not labeled by the manufacturer for individual dispensing. To circumvent this issue, some retail pharmacies dispense and bill for a full carton of insulin pens. If a patient’s health plan denied a claim because of a day supply limit, the pharmacy would reduce the day supply to conform with the plan day supply limit without adjusting the quantity of the insulin dispensed (37). This resulted in dispensing additional insulin pens in greater quantities than required for patients during a fill period.

The United States filed a health care fraud lawsuit against Walgreens for improperly billing federal health care programs using this billing practice. A settlement occurred in 2019, and Walgreens was required to pay $269.2 million to resolve allegations that it improperly billed federal health care programs for thousands of insulin pens that were not required (38,39). In November 2019, the FDA approved labeling revisions to emphasize the dispensing of insulin pens in the original sealed carton.

Individual community pharmacies and pharmacy corporations will have their own policies for handling insulin pen dispensing, breaking boxes, and addressing day supply issues. However, many pharmacists will submit for or call a patient’s insurance company to request an override for the day supply limit, and this approval is at the discretion of the insurance company (40). The majority of insulin pen cartons contain two to five pens; however, the FDA approved the first single-pen carton (for the glargine biosimilar product Semglee) on 11 June 2020 (41). Whether other insulin manufacturers will relabel pens for individual sale is unknown.

Generic Versus Biosimilar Insulin

When insulin was first manufactured in 1923, it was isolated from pigs and cows and thus was considered a “biologic” medication, defined as “a large, complex molecule often made from living cells and tissue” (3). However, the FDA regulated insulin as a drug under the Federal Food, Drug, and Cosmetic Act (3). For companies to produce a generic version of a drug, they must prove that the generic drug is the same as the reference product. This includes active ingredients, dosages, safety, strength, route, duration of action, and indication (42). Because insulin was considered a drug but did not fit the normal classification of a drug, the complexity of the amino acid structure and the multitude of studies required to prove equivalency to the reference product were costly and time-consuming and thus not financially feasible for companies to replicate as generics. The other reason for the lack of generic competition is that the insulin-manufacturing companies were able to improve on insulin products over time (e.g., by prolonging action, improving purity, or using recombinant technology), which resulted in additional patents extending patent protection beyond the original patent expiration date (2).

The Biologic Price Competition and Innovation Act of 2009 created a pathway for the approval of generic biologics, also known as “biosimilars” (3). Companies that want a biosimilar product to be considered a substitution for its reference product must prove that the biosimilar will have the same clinical results. Unlike generic drugs that are identical to the reference product, biosimilars just need to prove similar results (42,43). Unfortunately, insulin was not considered in the biologic framework at that time, and no insulin products could be a reference product for a biosimilar version (42,43). A change in this distinction for insulin occurred in March 2020 as part of the Affordable Care Act, specifically the Biologic Price and Competition Act (3). Per FDA guidance, all “rollover” insulin products (those already on the market) would be designated as stand-alone products when the transition occurred. In other words, none would become interchangeable biologics. However, all insulins on the market after March 2020 would be considered biologics, allowing for the development of interchangeable products.

The first interchangeable biosimilar insulin product was approved in July 2021. Semglee (insulin glargine-yfgn) is both biosimilar to and interchangeable with the reference product (insulin glargine) (44). This distinction gives community pharmacists the ability to switch to the less expensive biosimilar version of the insulin without requesting approval from the prescribing physician unless the physician documents on the prescription that the original reference product must be used.

For individuals without prescription drug coverage, human insulins are available as over-the-counter (OTC) products that do not require a prescription. Regular, NPH, and premixed 70/30 isophane and short-acting regular insulin can be purchased without a prescription in 49 states (45). (Indiana banned the sale of OTC insulin in 2014.) These specific insulins were on the market before the Federal Food, Drug, and Cosmetic Act of 1938, which required some drugs, including insulins, to be FDA-approved and classified as “legend” or “prescription” drugs. Legend drugs require a valid prescription from a licensed practitioner to be filled, whereas these specific insulins were “grandfathered in” and can still be sold without a prescription (46).

Although having insulin readily available for all patients, including those without insurance, is a good thing, there are some concerns regarding regulations for storage of these products and the potential for counterfeiting through the supply chain. A 2021 survey found that only 15 states require a license for the wholesale distribution of OTC products, including nonprescription insulin. Nonprescription insulin is also not included in the federal Drug Supply Chain Security Act of 2013, which requires traceability of products to protect the integrity of the drugs from adulteration and counterfeiting.

To help ease the cost of insulin for consumers, insulin manufacturers are developing their own authorized generic insulin products; these products are not considered “A-B rated,” but are considered “therapeutically equivalent” to the brand-name product and are often available for half the price (47). A-B rated products are drugs the FDA considers to be therapeutically equivalent and also to have adequate in vivo and/or in vitro evidence supporting their bioequivalence (48). Some brand-name companies developed partnerships with community drug chains to manufacture insulin products exclusively for those chains at a discounted price (46). Walmart’s private label ReliOn Novolog insulin (insulin aspart) is manufactured by Novo Nordisk and is available in pens and vials for 58–75% of the cash price of the branded product (49). The legality of substituting authorized generics for their brand-name reference product is controlled at the state level, and pharmacists must follow state laws, company policies, and insurance regulations when filling prescriptions for agents that are considered therapeutically equivalent (43). HCPs are likely to see more insulin product substitutions in the future.

Conclusion

The landscape around insulin and its available preparations, new technologies, and cost and coverage issues has changed dramatically since its discovery in 1921. Various formulations and delivery modalities have altered the way HCPs treat their insulin-requiring patients, and this, in turn, has led to improvements in patient care. Awareness of the complexities surrounding insulin prescribing is invaluable to today’s HCPs. Understanding the history of insulin manufacturing, relevant federal and state laws, and pharmacy-level constraints can improve insulin prescribing. HCPs who treat people with diabetes can improve patient care by selecting the optimal insulin product, delivered in the most appropriate device, to meet each patient’s needs. To accomplish this goal, HCPs must be aware of all available insulin and insulin delivery options.