Intravenous infusions of diluted insulin (human, regular) are used to treat and manage patients in urgent and critical situations such as diabetic ketoacidosis or hyperglycemia during septic shock. Historically, these infusions required manual sterile admixture by the pharmacy department, as a premix insulin infusion product was not commercially available.
Insulin is recognized by the Institute for Safe Medication Practices (ISMP) as a high-alert medication in acute care settings, due to the heightened risk of causing significant patient harm when the medication is used in error. Therefore, many institutions have implemented an independent double check of compounded insulin infusions to mitigate risk; however, ISMP states that these independent double checks are not always the optimal error-reduction strategy or may not be practical in all settings.1 Thus, a more streamlined and safe approach to providing intravenous infusions of diluted insulin is warranted. In June of 2019, the FDA approved the first premixed insulin infusion product, branded as Myxredlin, providing institutions a safe alternative to manual admixture of diluted insulin infusions.
Benefits of Premix Insulin Infusions
There are distinct advantages and safety benefits to using ready-to-administer (RTA) IV premixes compared to manually admixed preparations, including sterility assurance, quality control, extended shelf life, and administration safety with bar code verification. ISMP’s Guidelines for Safe Preparation of Compounded Sterile Preparations state that “ . . . To the maximum extent possible, COMMERCIALLY-PREPARED, premixed parenteral products and unit dose syringes are used versus manually compounded sterile preparations.”2
In 2018, the FDA released a compounding guidance document, Compounded Drug Products That Are Essentially Copies of a Commercially Available Drug Product Under Section 503A of the Federal Food, Drug, and Cosmetic Act, which states, “To qualify for exemptions under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act), a drug product must be compounded by a licensed pharmacist or physician who does not compound regularly or in inordinate amounts of any drug products that are essentially copies of a commercially available drug product . . .”.3 RTA IV premixes are prepared in manufacturing facilities following current good manufacturing practices (cGMP) outlined in 21 CFR Part 210 and 211, with no exemptions to the FD&C Act offered. These practices provide superior sterility assurance and quality control when compared to the practice settings of many 503A compounding pharmacies. For these reasons, FDA further comments that [manually compounding essentially copy drug products] is “ . . . A practice [that] would create significant public health risks because patients would be unnecessarily exposed to drug products that have not been shown to be safe and effective and may have been prepared under substandard manufacturing conditions.”3
Review of manual admixture practices for insulin infusions reveals variation by institution and even by personnel. For example, when preparing an insulin 100 units in 100 mL of 0.9% sodium chloride (1 unit/mL) IV bag, multiple admixture practices have been observed (see TABLE 1). Overfill volume in commercially prepared IV bags varies by manufacturer and is usually given as a range (eg, 5-10 mL for a 100 mL IV fluid bag manufactured by Baxter). For this purpose, there exists some margin of error when calculating the final volume and final drug concentration.
Rocchio, et al studied the stability of regular human insulin extemporaneously prepared in 0.9% sodium chloride in a polyvinyl chloride bag. The preparation methods used in the study follow method “C” in TABLE 1, which involves removing 8 mL of diluent from a 100 mL bag and then adding 1 mL (100 units) of insulin to the bag. Three prepared bags were analyzed using high-performance liquid chromatography; at 0 hours the insulin concentrations were 0.92 units/mL, 0.91 units/mL, and 0.92 units/mL.4
This study demonstrates that even when removing the mean overfill volume and additive volume that the concentration is still less than expected and labeled by up to 9% (0.91 units/mL compared to 1 unit/mL). Thus, not accounting for overfill or additive volume during preparation may yield a concentration outside of the acceptable 10% margin of error (ie, <0.9 units/mL). A conventionally manufactured product will not experience this same degree of error, as manufacturing practices must past strict quality assurance testing prior to being released and are not prepared using premixed base fluid bags, allowing for more accurate preparation.
Bar Code Safety
Because premix IVs arrive from the manufacturer with the NDC embedded in the bar code, there is a built-in safety net that ensures the appropriate product is administrated to the right patient via BCMA. While many advancements have occurred within pharmacy to introduce bar code medication preparation (BCMP) in the cleanroom for all sterile admixtures (ie, bar code verification of each ingredient and diluent in a manual admixture), hospital adoption of this technology has been rather slow. Without BCMP in place, BCMA cannot catch most compounding errors, and since most infusions consist of a clear drug added into a clear fluid, visual inspection will not catch these errors either. Switching to a premix IV product that contains a bar code from the manufacturer adds an immediate improvement to the safety of the product.
Shelf Life and Storage
Insulin infusions exhibit physical denaturation and chemical modifications, thus the literature supports various beyond-use dates (BUDs), from 24 hours to 14 days at refrigerated temperatures. Manual admixture of IV preparations in a 503A compounding pharmacy must follow USP <797> standards for application of a BUD, which are based on the rate limiting factor of sterility or stability. In most 503A settings, performing a sterility test on sterile, manually admixed preparations is not feasible; thus, USP <797> offers maximum BUDs under certain conditions, outlined as low-risk, medium-risk, and high-risk. These conditions offer up to a 14 day refrigerated BUD (low-risk) or 9 day refrigerated BUD (medium-risk). These restricted BUDs and the refrigeration requirement may prevent storage of finished preparations in the ICU or ED for quick access given the likelihood of significant waste from product expiration.
Myxredlin can be maintained in the refrigerator for long-term storage (until its labeled expiration date); in addition, its labeling allows room temperature storage for up to 30 days. This creates the opportunity to store the product in key areas throughout the hospital for quick access and will result in less waste from expired product compared to the manually prepared admixture.
Per the ASHP IV Adult Continuous Infusion Guidelines, the standardized continuous infusion concentration of insulin (regular) is 1 unit/mL.5 Further, the guidelines indicate that a bag size of 100 units/100 mL NS or 250 units/250 mL NS can be used. An analysis can be performed to determine which bag size is most appropriate for the acuity of the patients and provider or guideline dosing. For our institution, over 85% of patients on insulin infusions receive less than 100 units in a given 24-hour period, thus supporting the 100 units/100 mL NS bag as the optimal standard bag size. After analyzing infusion rates and volumes over time, our institution changed insulin infusion bag size from 250 units to 100 units, which led to a significant reduction in costly insulin waste.
When a new premix IV comes to market, it is prudent to review the financial impact prior to switching from the equivalent manual admixture to the premix product. A comprehensive pharmacoeconomic analysis should be performed; simply comparing the drug cost of the manual admixture preparation to the price of the premix product is a flawed approach that may lead to false conclusions.
Considering the complexities of manual admixture, the analysis should include the cost of the diluent bag, materials (needles, syringes, labels, etc), technician labor (preparation, delivery), pharmacist labor (verification), waste (expired product, errors), and other miscellaneous cleanroom costs (sterile gloves, gowns, etc). Further, consider the allocation of time (technician and pharmacist labor) that can be redeployed to other tasks, or to spend more focused time and attention on critical life-saving preparations. Lastly, the analysis should also incorporate other objective and subjective measures where the premix product has advantages. Consider if the placement of the premix bags at room temperature in critical areas of the hospitals will reduce turnaround times (from provider ordering to drug administration) and ultimately improve the quality of patient care.
When Myxredlin first entered the market, the label on the infusion bag was identified by ISMP as having opportunities for improvement. The word MYXREDLIN was prominent and beneath this text insulin human was stated in a much smaller font size. ISMP made a recommendation to increase the size of the text to minimize look-alike errors. In addition, ISMP recommended that until the labels are updated by the manufacturer to apply an auxiliary label (ie, Insulin on the front and back of the container).6 The risk of look-alike errors highlights the importance of BCMA, to provide an additional safety net for visual mix-up errors through bar code verification prior to administration. Recently, the manufacturer revised the labeling consistent with ISMP’s recommendations by prominently displaying “Insulin Human” in a red color band with an increased font size; an additional label printed on the back of the bag states “CONTAINS INSULIN”.7
Premix IVs offer distinct advantages over manual admixtures, including increased sterility assurance, quality control, bar code safety, extended shelf life, and can provide optimal bag sizes. After performing a comprehensive pharmacoeconomic analysis, an institution can realize the financial, objective, and subjective benefits of adding the premix product to the institution’s formulary. Sterile manual admixture of IV infusions exists within pharmacy as conventionally manufactured products are not available for all medications. Thus, when a premix IV comes to market, institutions should make it a priority for the safety of their patients that to the maximum extent possible, commercially prepared, premixed parenteral products are used versus manually compounded sterile preparations.
Kevin N. Hansen, PharmD, MS, BCPS, BCSCP, the assistant director of pharmacy at Moses H. Cone Memorial Hospital, provides oversight and leadership for pharmaceutical compounding and perioperative services pharmacy. He graduated from the Lake Erie College of Osteopathic Medicine with a Doctor of Pharmacy degree and received an MS in Pharmaceutical Sciences from the University of North Carolina Eshelman School of Pharmacy.
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