AHFS Class:

68:20.08 Insulins

Generic Name

• Insulin

Regular insulin is available in 10-mL vials and 1.5-mL prefilled syringes and syringe cartridges at a concentration of 100 units/mL. Human insulin is produced using recombinant DNA technology. Regular concentrated insulin (Lilly) also is available in 20-mL vials containing 500 units/mL. Glycerin 1.4 to 1.8% and phenol or cresol 0.1 to 0.25% also may be present.^1(1/08); ⁴

Several modified forms of insulin (Isophane, Lente, etc.) are available, each having a characteristic onset of action, time to peak effect, and duration of action.⁴

Adequately mixing these products is necessary prior to use, but vigorous shaking may entrain air bubbles that could interfere with accurate dosing. Gentle shaking of the vial combined with end-over-end inversion and rolling in the palms has been suggested.²²⁷⁰

pH

All regular insulin products have a neutral pH of approximately 7 to 7.8.⁴; ²⁶¹

Trade Name(s)

HumuLIN R, NovoLIN R

Regular insulin usually is administered by subcutaneous injection into the thighs, arms, buttocks, or abdomen, with sites rotated. Syringes calibrated for the particular concentration of insulin to be given must be used. Regular insulin also may be administered intramuscularly or by intravenous infusion, usually diluted in sodium chloride 0.9%. Regular insulin is the only form of insulin that can be given intravenously.⁴

Care is required when adding insulin to infusion solutions, especially in flexible containers. Adding insulin to a plasma expander carrier solution hanging in the use position resulted in stratification, with the insulin floating to the top. Little insulin was delivered initially, and 87% of the insulin appeared in the last 28% of the solution. Repeated inversion and agitation of the container to effect thorough mixture eliminates this stratification, yielding an even distribution and a constant delivery concentration.⁸⁵

Disposable insulin syringes are usually siliconized. Reuse of disposable plastic insulin syringes (Plastipak Microfine II, Becton Dickinson) has resulted in contamination of vials of insulin with silicone oil, causing a white precipitate and impairment of biological effects and is not recommended. In a test of insulin from several sources, repeated drawing of the insulin into the disposable syringes and then expulsion of it back into the vials introduced substantial amounts of silicone oil; a white precipitate formed within 12 hours at 8°C.¹¹¹⁰

Regular insulin should be stored under refrigeration and protected from freezing.^1(1/08); ⁴ Although refrigerated storage is required, some manufacturers have stated the drug may be stored at room temperature for 28 to 30 days.²⁷⁴⁵; ²⁷⁶⁹ Freezing of insulin products may alter the protein structure, decreasing concentration.⁵⁵⁹ In one study of several insulin products, 1 cycle of freezing for 45 hours followed by slow thawing at 21°C or rapid thawing in a water bath at 37°C did not result in a loss of bioactivity. However, microscopic examination revealed particle aggregation, and some crystal damage had occurred.⁶⁸⁰

The stability of regular insulin (Novo Nordisk) was evaluated under simulated shipping conditions. Sample vials were packaged in both insulated and non-insulated mailers and packaged with either two 12-oz. frozen gel packs for simulated summer mailing or one 12-oz. frozen gel pack for simulated winter shipping. The evaluation was conducted for simulated transit periods ranging from 24 hours to 120 hours (overnight air delivery to ground delivery). Visual inspection found no change in appearance in any of the samples tested. Microscopy found no formation of aggregates. No loss of insulin content occurred in any of the samples with any of the shipping methods and conditions. Size exclusion chromatography found little or no change in high-molecular-weight protein content. The regular insulin remained within USP specifications with all of the shipping methods and time periods studied.²⁷⁶⁹

As with other protein and peptide products, insulin aggregation with possible reduced bioactivity can be a problem. Aggregates have been found to form in a variety of infusion devices and under various storage conditions, including static storage and continuous rotational or reciprocating motion.¹⁹⁴⁸; ¹⁹⁹⁵; ²⁴⁰⁶ Aggregation may occur at air-water interfaces. Such interfaces have been generated by turbulence, such as shaking and repeatedly passing insulin through a syringe and needle. With sufficient vigor, both actions can turn the insulin turbid from insoluble aggregates.¹⁹⁴⁸ In addition, contact with silicone rubber appears to promote insulin aggregation.¹⁹⁹⁵

Factors that increase the formation rate of insulin transformation products (such as deamidated insulin, covalent dimers, and higher oligamers) in beef and human insulin products were evaluated during 6 months of storage. A low rate of transformation product appeared at 4°C. Higher temperatures, as might occur when insulin is carried in a shirt pocket or car glove compartment, accelerated this production (especially for human insulin) and also fibril formation. Exposure to light increased the dimer and higher oligamer content. Insulin should not be exposed to direct sunlight or subjected to vibration or extremes of temperature.¹⁶⁶³

The appearance of transformation products was found to be 2- to 3-fold greater when using polyvinyl chloride (PVC) administration sets compared to polyethylene and polypropylene infusion equipment. Furthermore, use of the PVC sets resulted in up to 30% reduction in the concentration of methylparaben, phenol, and m-cresol preservatives in insulin products.³¹¹

Regular insulin, containing 100 units/mL, is clear and colorless or almost colorless. The concentrated injection containing 500 units/mL may be straw colored. Discoloration, turbidity, or unusual viscosity indicates deterioration or contamination.⁴

Syringes

It has been stated that neutral regular insulin (and also NPH and Lente insulin) can be stored for 5 to 7 days under refrigeration in either glass or plastic syringes. Mixtures of these insulins also can be stored similarly.⁶⁷⁹

Insulin soluble, BP, 1.6 units/2 mL diluted in sodium chloride 0.9% was stored for 18 hours at room temperature in the following plastic syringes: Brunswick (Sherwood Medical), Plastipak (Becton Dickinson), and Sabre (Gillette U.K.). The first 2 syringes have polypropylene barrels; the Sabre has a combination polypropylene-polystyrene barrel. No significant loss of insulin occurred due to sorption. Significant (but unspecified) losses did occur when the concentration was reduced to 0.2 unit/mL, but the make of syringe did not influence this adsorption.⁷⁸⁴

No apparent degradation or binding occurred for at least 14 days when insulin, USP (Lilly), 100 units/mL was stored under refrigeration in 1-mL polypropylene syringes (Becton Dickinson).⁸⁰⁵

The soluble insulins Velosulin (Nordisk), Actrapid and Human Actrapid (Novo), Humulin S (Lilly), Neusulin (Wellcome), and Quicksol (Boots) in 1-mL 100-unit Plastipak syringes (Becton Dickinson) exhibited no loss in 29 days when stored at 4 and 20°C.¹²⁷⁵

Regular insulin human (Humulin R, 100 units/mL, Lilly), isophane insulin human (Humulin N, 100 units/mL, Lilly), and the combination product (Humulin N/R 70/30, Lilly) were evaluated for stability packaged in plastic syringes. Test samples of 0.4 mL of each insulin product were drawn into 1-mL polypropylene syringes (Plastipak, Becton Dickinson) and 1-mL polypropylene-ethylene copolymer syringes (Terumo) and stored for 28 days at 4 and 23°C. No loss of insulin from any insulin product occurred in either syringe type. However, the antibacterial preservatives present in the insulin formulations were lost, especially in the polypropylene syringes at room temperature. Storage under refrigeration to slow the loss of preservative as much as possible was recommended.¹¹²⁴

Infusion Pumps

Insulin solutions may form highly insoluble polymers. In areas having high shear rates such as the tubing, cannula, and needle, aggregation can lead to blockage. In low shear areas such as the insulin reservoir of implantable pumps, gentle agitation can lead to the formation of a cross-linked gel.¹¹¹²

Sorption

The adsorption of insulin to the surfaces of intravenous infusion solution containers, glass and plastic (including PVC, ethylene vinyl acetate [EVA], polyethylene, and other polyolefins), tubing, and filters has been demonstrated. Estimates of the loss range up to about 80% for the entire infusion apparatus, although varying results using differing test methods, equipment, and procedures have been reported. Estimates of adsorption of around 20 to 30% are common. The percent adsorbed is inversely proportional to the concentration of insulin. Other important factors are the amount of container surface area and the fill volume of the solution. The amount of insulin adsorbed varies directly with the available surface area and indirectly with the ratio of fluid volume to container capacity. The container material is a factor, with glass possibly adsorbing insulin more extensively than some plastics. Other factors influencing the extent of insulin adsorption include the type of solution, type and length of administration set, rate of infusion, temperature, previous exposure of tubing to insulin, and presence of albumin human, whole blood, electrolytes, and other drugs.²⁶⁶; ²⁶⁷; ²⁶⁸; ²⁶⁹; ⁴²⁰; ⁴²²; ⁴²³; ⁴²⁴; ⁴²⁵; ⁴²⁶; ⁴²⁸; ⁵³³; ⁶⁸¹; ⁶⁸²; ⁶⁸³; ⁶⁸⁴; ⁶⁸⁵; ⁶⁸⁶; ⁶⁸⁷; ⁶⁸⁸; ⁶⁸⁹; ⁶⁹⁰; ⁸⁵⁴; ⁹⁰⁸; ⁹⁰⁹; ⁹¹⁰; ⁹¹¹; ⁹¹²; ⁹¹³; ¹¹¹¹; ¹¹¹²; ¹²⁷⁴; ¹²⁸²; ¹⁴⁰⁸; ¹⁴⁹⁷; ¹⁶⁶⁴; ¹⁶⁶⁵; ²⁰⁷⁹; ²³⁰¹

The adsorption of insulin to container surfaces is an instantaneous process.²⁶⁷; ⁴²⁵; ⁹¹¹; ⁹¹²; ⁹¹³ However, the effect of adsorption on the deliverable amount of insulin appears to vary with time. Several investigators reported a dramatic initial drop in delivered insulin followed by a return to higher (although variable) levels. The bulk of the insulin adsorption apparently occurs in the first 30 to 60 minutes. Although flow rate does not influence total insulin binding, the plateau phase of delivered insulin may be reached more quickly at faster infusion rates.⁴²²; ⁴²⁴; ⁴²⁵; ⁴²⁶; ⁴²⁸; ⁶⁸⁷; ⁶⁸⁸; ⁶⁸⁹; ⁸⁵⁴; ²³⁰¹

In a study of insulin loss during simulated delivery to low-birth-weight infants, insulin 0.2 unit/mL was delivered at rates of 0.05 and 0.2 mL/hr through microbore PVC tubing and polyethylene-lined PVC tubing. During the early hours, the amount of insulin delivered through both types of tubing was much reduced, especially at the slower delivery rate. The authors indicated that this loss might contribute to the 14- to 24-hour delays in blood glucose normalization in these infants. The priming of microbore tubing with 5 units/mL of insulin for 20 minutes was suggested to accelerate the achievement of steady-state insulin delivery. The time courses of insulin delivery observed for representative unprimed and primed sets are presented in Table 1.²³⁰¹

Regular human insulin 0.1 unit/mL in sodium chloride 0.9% in VISIV polyolefin bags was tested for 24 hours at room temperature near 23°C. About 35% loss occurred, which is consistent with the drug’s potential for adsorption to surfaces.²⁶⁶⁰; ²⁷⁹²

Table 1. Approximate Amount of Insulin Delivered through Unprimed and Primed^a Administration Sets²³⁰¹

The addition of albumin human to infusion solutions helps to reduce the adsorption of insulin. The degree to which albumin human prevents adsorption is uncertain. Reported losses of insulin in albumin-containing solutions have varied from about zero to approximately 30%. However, most work indicates a substantial reduction in insulin adsorption.²⁶⁶; ²⁶⁷; ²⁶⁸; ²⁶⁹; ⁴¹⁸; ⁴²⁸; ⁶⁸³; ⁶⁸⁴; ⁶⁸⁵; ⁹⁰⁸; ⁹⁰⁹ Other additives such as vitamins, electrolytes, and drugs may also have a similar effect.⁴²⁵; ⁹⁰⁹; ⁹¹⁴

Other recommended approaches to avoiding or minimizing adsorption include adding a small amount of the patient’s blood to the insulin solution⁶⁸⁹; ⁶⁹⁰; ⁶⁹¹ and storing or flushing the administration apparatus with the insulin solution to saturate the set prior to administration.⁴²⁸; ¹¹¹¹; ²³⁰¹ Addition of extra insulin to compensate for the losses has also been suggested.¹¹¹² As an alternative, administration of insulin using a syringe pump with a short cannula has been recommended. This procedure will reduce the surface area in relation to the amount of insulin present.¹⁰³³

The clinical significance of this adsorption is uncertain. Some clinical studies indicated no relevant effect on the success of therapy.⁴¹⁵; ⁴²⁷; ⁶⁸⁵ Some investigators felt that the importance of insulin adsorption to the surfaces of the infusion container and tubing may be a moot point since the dosage is individualized on the basis of blood and urine glucose determinations. Simply adding more insulin may saturate binding sites and yield the desired response.²⁷⁰; ²⁷¹; ⁸⁵⁴; ⁹⁰⁹

Still others indicated that the adsorption may indeed be relevant for solutions with an insulin content of less than 100 or 200 units/L.⁴²⁴; ⁴²⁶; ⁴²⁸; ⁹⁰⁸; ²³⁰¹

If the apparent dose of intravenous insulin is used as the basis for determining the subsequent dose upon discontinuing the intravenous one, then a potential for dosing error exists. The actual amount of insulin being administered could be substantially less than the apparent amount.⁵³³

Whether one attempts to prevent insulin adsorption or not, it does not appear to be possible to add an amount of insulin to an infusion solution and know precisely what portion of that amount will actually be given to the patient. Monitoring the patient’s response to therapy and making the appropriate adjustments on the basis of that response are, therefore, of prime importance.⁶⁹⁰; ⁸⁵⁴; ¹⁶⁶⁴

Implantable Pumps

Insulin, regular human (Genapol, Hoeschst-Roussel) 400 units/mL with heparin sodium 500 units/mL was evaluated in MIP 2001 implantable pumps (MiniMed) at 37°C for 3 months. The drug solution remained visually clear, but the insulin content dropped to 65% of the initial amount. The activity of heparin declined by even more. Only 45% remained after 3 months. The losses were attributed to the shaking that occurred during use rather than temperature, interaction with pump materials, or interaction of the 2 drugs with each other.²³⁹

Standardize 4 Safety

One or more standardized concentrations for this drug have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. (See Standardize 4 Safety in Users Guide.) Recommendations developed to date through this initiative are available at www.ashp.org/pharmacy-practice/standardize-4-safety-initiative.

Table 2: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Insulin (regular)³⁶³⁵; ³⁶³⁶

^a DKA protocols may require units/kg per hour.

Solution Compatibility

Additive Compatibility

Drugs in Syringe Compatibility

Y-Site Injection Compatibility (1:1 Mixture)

Additional Compatibility Information

Mixing Insulin Products

Mixing of the various types of insulin has been utilized. The following compatibility results have been cited:¹⁰⁷⁶

^a Includes Humulin BR, NPH, protamine zinc, Velosulin insulins.

It has been stated that neutral regular insulin may be combined with modified insulin in any proportions.²⁶³; ²⁶⁴ However, losses of soluble insulins when mixed with zinc and isophane insulins were reported. These losses generally ranged from about 20 to 50% but were as high as 99%, depending on the ratio and sources of the 2 insulins in the mixture. The reaction occurred within the first 90 to 120 seconds after mixing, with no further losses occurring after this time. This phenomenon could explain clinical reports of failure to control postprandial blood sugar levels.¹²⁷⁵

The loss of solubility when short-acting insulins were mixed in ratios of 1:1, 1:2, 1:3, and 1:5 with long-acting insulins was reported. Iletin II Regular (Lilly) was mixed with Iletin II Lente, NPH, or Ultralente (Lilly). Actrapid (Novo) was mixed with Monotard (Novo). Velosulin (Nordisk) was mixed with Insulatard (Nordisk). The mixtures were centrifuged after storage times of approximately 20 minutes and 75 seconds. The level of soluble short-acting insulin in the supernatant was determined. In a 1:1 ratio, no significant loss of solubility occurred with the Iletin II Lente combination within 20 minutes and with the Actrapid-Monotard combination in 75 seconds. All other combinations, ratios, and time periods had losses ranging from 10 to 75%. The worst losses were experienced with the highest ratios of long-acting insulins and with the longer time period. The method used to prolong insulin action (precipitation) might affect the solubility of the short-acting insulin when admixed.¹¹⁵⁶

The loss of initial hypoglycemic effect when Actrapid HM (Novo) was mixed with Ultratard HM (Novo), an ultralente insulin, for 5 minutes before injection was noted. The authors recommended not mixing the 2 types of insulin to preserve the rapid hypoglycemic effect of regular insulin.⁷³

Octreotide

Insulin levels in a 3-L bag of parenteral nutrition solution showed a marked reduction when octreotide 150 mcg was added to the container. Sample parenteral nutrition solutions, with and without octreotide, were prepared with regular insulin 15 units/3-L bag. Subsequent analysis found an insulin level of 3.5 units/L in the plain parenteral nutrition solution, an amount consistent with the losses occurring due to surface adsorption. However, in the parenteral nutrition solution containing octreotide, the insulin level was only 0.6 unit/L. The reason for this potential incompatibility is not known.¹³⁷⁷

Peritoneal Dialysis Solutions

Insulin 4, 10, 20, and 40 units/L was evaluated in the following Baxter peritoneal dialysis solutions in PVC and Clear-Flex polyolefin containers:

• Dianeal PD-4 with 1.36% dextrose in PVC containers
• Physioneal 40 with 1.36% dextrose in PVC containers
• Physioneal 40 Clear-Flex with 1.36% dextrose in Clear-Flex

In Dianeal PD-4, more than 90% of the insulin concentration remained over 24 hours. The insulin 10, 20, and 40 units/L in Physioneal 40 retained more than 90% of the insulin concentration over 6 hours and more than 80% over 24 hours. The insulin 4 units/L in Physioneal 40 retained more than 90% of the insulin concentration over 3 hours and more than 70% over 24 hours. No difference was found between the results in PVC and Clear-Flex containers.²⁶⁴⁷

For a list of references cited in the text of this monograph, search the monograph titled References.

ASHP^® Injectable Drug Information^TM. Selected Revisions March 31, 2024. © Copyright, 2024. American Society of Health-System Pharmacists^®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.