Administration 
Insulin Human (Regular)
Insulin human (regular) injection is usually administered by subcutaneous injection.5,12,71,82,88 Insulin human (regular) also may be administered IV or IM† under medical supervision with close monitoring of blood glucose and potassium concentrations to avoid hypoglycemia or hypokalemia.125
Parenteral Administration
Excessive agitation of the vial prior to withdrawing the insulin dose should be avoided since loss of potency, clumping, frosting, or precipitation may occur.67,101 Warming refrigerated insulin to room temperature prior to use will limit local irritation at the injection site.67,101
For IV infusion, insulin human (regular) injection is usually diluted to a concentration of 0.05-1 unit/mL in 0.9% sodium chloride or 5 or 10% dextrose injection with 40 mEq/L of potassium chloride in polypropylene infusion bags.54,55,125
The manufacturer of Novolin® R states that the injection should not be used in continuous infusion pumps, as such use may result in adsorption onto pump catheters.125
When concentrated (U-500) insulin human (regular) injection is used in patients with marked insulin resistance (i.e., daily insulin requirements exceeding 200 units), extreme caution must be exercised in dosage measurement because inadvertent overdosage may result in irreversible insulin shock. The manufacturer further warms that serious consequences may result if this concentrated injection were used other than under constant medical supervision.
Standardize 4 Safety
Standardized concentrations for insulin (regular) have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 249,250Multidisciplinary expert panels were convened to determine recommended standard concentrations. 249,250Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 249,250 For additional information on S4S (including updates that may be available), see [Web]249,250 .
Table 1: Standardize 4 Safety Continuous IV Infusion Standard Concentrations for Insulin (Regular)249,250
Patient Population | Concentration Standards | Dosing Units |
|---|
Adults | 1 unit /mL | units/houra |
Pediatric patients (<50 kg) | 0.2 units/mL | units/kg/hour |
| 1 unit/mL | |
aDKA protocols may require units/kg/hour
Isophane Insulin Human
Parenteral Administration
Isophane insulin human suspension is usually administered subcutaneously;54,55,75,84 this form of insulin must not be administered IV.54,55 Since the active ingredient in isophane insulin suspensions is in the precipitate and not in the clear supernatant liquid, the vial should be gently agitated to assure a homogeneous mixture for accurate measurement of each dose.6,8,75,84,92,93 This may be done by slowly rotating and inverting or carefully shaking the vial several times before withdrawal of each dose.6,8,75,84 Vigorous shaking should be avoided since this causes frothing, which interferes with correct measurement of a dose.6,8
Preparations of isophane insulin suspensions that are slowly injected subcutaneously may clog the tip of the needle, resulting in an inability to complete the injection.6,8 Since this is less likely to occur when the insulin is injected subcutaneously more rapidly, the dose should be injected over a period of less than 5 seconds.6,8,55
When a compatible delivery device is used for subcutaneous injection of isophane insulin human suspension (e.g., Humulin® N pen) or the fixed combination containing insulin human (regular) injection and isophane insulin human suspension (Humulin® 70/30 Pen®), the accompanying labeling should be consulted for proper methods of assembly, administration, and care.117,119
Dosage
Diabetes Mellitus
Any change in insulin preparation or dosage regimen should be made with caution and only under medical supervision.5,6,7,8,80,88,93,94 Changes in strength, brand, type, and/or method of manufacture may necessitate a change in dosage.5,6,7,8,77,78,79,80,88,93,94 Illness, particularly nausea and vomiting, and changes in eating patterns may alter insulin requirements.5 Although it is not possible to clearly identify which patients will require a change in dosage when therapy with a different preparation is initiated, it is known that a limited number of patients will require such a change.5,6,7,8 Adjustments may be needed with the first dose or may occur over a period of several weeks.5,6,7,8
Parenteral Dosage
Dosage of insulin human as the injection is always expressed in USP units.5,6,7,8,12 Dosage of insulin should be individualized to attain optimum therapeutic effect.5,6,7,8,12
Initial total daily insulin dosages in adults and children with type 1 diabetes mellitus range from 0.2-1 units/kg.125,251,252,253,254,255 Children with newly diagnosed type 1 diabetes usually require an initial total daily dosage of approximately 0.5-1 units/kg; the dosage requirement can be much lower during the period of partial remission.125,255 In severe insulin resistance (e.g., puberty, obesity), the daily insulin dosage may be substantially higher.125 In patients with type 2 diabetes mellitus, the initial total daily insulin dosage ranges from 0.2-0.4 units/kg.125
Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic States
Because it has a relatively rapid onset of action and can be administered IV, regular insulin (e.g., insulin human [regular]) is the insulin of choice in the treatment of diabetic emergencies such as diabetic ketoacidosis or hyperosmolar hyperglycemic coma.113 Prompt correction of hyperglycemia with adequate doses of insulin, correction of dehydration and electrolyte imbalances with IV fluid and electrolyte therapy, and frequent monitoring of clinical and laboratory data are essential to successful treatment of these hyperglycemic crises.113 Hydration status should be carefully monitored in patients with diabetic ketoacidosis or hyperosmolar hyperglycemia, and 0.9% sodium chloride injection generally should be infused IV (in the absence of cardiac compromise) if serum sodium concentrations (corrected for the effect of hyperglycemia) are low; 0.45% sodium chloride injection may be used if serum sodium concentrations are normal or elevated.113 Since diabetic ketoacidosis often is associated with hypokalemia, the possibility of potassium imbalance should be evaluated and, if present, corrected before administration of insulin as long as adequate renal function is assured.113 Blood pH should be determined, and if acidosis is severe (blood pH less than 7), patients should receive IV sodium bicarbonate until blood pH exceeds 7.113
Adults
For the treatment of moderate to severe diabetic ketoacidosis (plasma glucose exceeding 250 mg/dL with arterial pH of 7-7.24 or less and serum bicarbonate of 10-15 mEq/L or less) or hyperosmolar hyperglycemia in adults, the American Diabetes Association (ADA) recommends a loading dose of 0.15 units/kg of regular insulin by direct IV injection, followed by continuous IV infusion of 0.1 units/kg per hour.113 Plasma glucose should decrease at a rate of 50-75 mg/dL per hour.113 If plasma glucose concentrations do not fall by 50 mg/dL within the first hour of insulin therapy, the insulin infusion rate may be doubled every hour, provided the patient is adequately hydrated, until plasma glucose decreases steadily by 50-75 mg/dL per hour.113 When a plasma glucose concentration of 250 or 300 mg/dL is achieved in patients with diabetic ketoacidosis or hyperosmolar hyperglycemia, respectively, the insulin infusion rate may be decreased to 0.05-0.1 units/kg per hour.113 Once these target glucose concentrations have been achieved, infusion with 0.9% sodium chloride injection may be changed to dextrose 5% with 0.45% sodium chloride solution and administered with insulin to maintain serum glucose concentrations between 150-200 mg/dL in patients with diabetic ketoacidosis or 250-300 mg/dL in those with hyperosmolar hyperglycemia.113 Serum determinations of electrolytes, BUN, creatinine, osmolality, and glucose should be made every 2-4 hours until the patient is stable; monitoring of serum osmolality and cardiac, renal, and mental status is particularly important in patients with renal or cardiac compromise to avoid iatrogenic fluid overload.113 The rate of insulin administration or the concentration of dextrose may need to be adjusted to maintain glucose concentration until resolution of diabetic ketoacidosis (i.e., serum glucose less than 200 mg/dL, venous pH exceeding 7.3, serum bicarbonate of at least 18 mEq/L) or hyperosmolar hyperglycemia (i.e., patient mentally alert, serum osmolality of 315 mOsm/kg or less).113
For the treatment of mild diabetic ketoacidosis (plasma glucose exceeding 250 mg/dL with an arterial pH of 7.25-7.3 and serum bicarbonate of 15-18 mEq/L), ADA states that regular insulin given subcutaneously or IM† every hour is as effective as IV insulin administration in reducing hyperglycemia and ketonemia.113 A loading dose of regular insulin 0.4-0.6 units/kg may be administered in 2 doses, with 50% given by direct IV injection and 50% by subcutaneous or IM† injection.113 After the loading dose, 0.1 units/kg per hour of regular insulin may be given subcutaneously or IM†.113
After resolution of diabetic ketoacidosis (i.e., plasma glucose less than 200 mg/dL, venous pH exceeding 7.3, serum bicarbonate of 18 mEq/L or greater) or hyperosmolar hyperglycemia in patients who are unable to eat, IV insulin and fluid replacement is continued, and subcutaneous regular insulin may be given as needed every 4 hours.113 Regular insulin may be given subcutaneously in 5-unit increments for every 50 mg/dL increase in blood glucose concentrations above 150 mg/dL, to a dose of up to 20 units of insulin for a blood glucose of 300 mg/dL or higher.113 When the patient is able to eat, a multiple-dose, subcutaneous insulin regimen consisting of a short- or rapid-acting insulin and an intermediate- or long-acting insulin is initiated.113 Regular insulin is continued IV for 1-2 hours after initiation of the subcutaneous insulin regimen to ensure adequate plasma insulin concentrations during the transition from IV to subcutaneous insulin; otherwise, abrupt discontinuance of IV insulin with the institution of delayed-onset subcutaneous insulin may lead to worsened glycemic control.113 Patients with known diabetes mellitus may reinstitute the insulin regimen they were receiving before the onset of diabetic ketoacidosis or hyperosmolar hyperglycemia, and the regimen may then be adjusted further as needed for adequate glycemic control.113
Patients with newly diagnosed diabetes mellitus should receive a total insulin dosage of 0.5-1 units/kg daily as part of a multiple-dose regimen of short- and long-acting insulin until an optimal dosage is established.113 Some patients with newly diagnosed type 2 diabetes mellitus may be managed with diet therapy and oral antidiabetic agents following resolution of hyperglycemic crises.113
Pediatric Patients
In pediatric patients (younger than 20 years of age) with diabetic ketoacidosis or hyperosmolar hyperglycemia, ADA recommends initiation of insulin therapy with an IV infusion of regular insulin at a rate of 0.1 units/kg per hour; an initial direct IV injection of insulin is not recommended in pediatric patients.113 If IV access is unavailable, insulin may be given IM in an initial dose of 0.1 units/kg, followed by 0.1 units/kg per hour subcutaneously or IM until acidosis is resolved (i.e., venous pH exceeds 7.3, serum bicarbonate concentration exceeds 15 mEq/L).113 Upon resolution, the insulin infusion rate should be decreased to 0.05 units/kg per hour until subcutaneous replacement insulin therapy (using a multiple-dose regimen of short- and intermediate-acting insulins) is initiated.113 When a serum glucose concentration of 250 mg/dL is achieved in pediatric patients with diabetic ketoacidosis or hyperosmolar hyperglycemia, dextrose 5-10% with 0.45-0.75% sodium chloride injection is administered to complete rehydration in 48 hours and maintain serum glucose concentrations between 150-250 mg/dL.113 Serum electrolyte and glucose concentrations should be determined every 2-4 hours until the patient is stable.113 After diabetic ketoacidosis in pediatric patients has resolved, subcutaneous insulin may be initiated at a dosage of 0.5-1 units/kg daily in divided doses ((2/3) of the daily dosage in the morning [(1/3) as short-acting insulin, (2/3) as intermediate-acting insulin] and (1/3) in the evening [½ as short-acting insulin, ½ as intermediate-acting insulin]).113 In pediatric patients with newly diagnosed diabetes mellitus, regular insulin 0.1-0.25 units/kg may be given every 6-8 hours during the first 24 hours to determine insulin requirements.113
Pharmacology
Studies in animals, healthy adults, and patients with type 1 (insulin-dependent) diabetes mellitus have shown insulin human to have essentially identical pharmacologic effects compared with purified pork insulin (no longer commercially available in the US).12,13,17,18,19,20,21,22,23,38,39,40 Potency of insulin human, with respect to its efficacy for replacement therapy in patients with type 1 diabetes mellitus, is similar to that of purified pork insulin.18,19,20,21,23,41 .
Pharmacokinetics
The pharmacokinetic profile of insulin human has been shown to be essentially identical to that of purified pork insulin (no longer commercially available in the US).13,17,18,19,20,21,22,25 No clinically important differences in total body clearance rates, plasma half-lives, apparent volume of distribution, or effect on blood glucose concentration have been observed following administration of insulin human or purified pork insulin.13,21 In vitro studies have shown that the binding affinities for human erythrocyte receptors and for receptors on porcine hepatocytes are similar for insulin human and purified pork insulin.21
Chemistry and Stability
Chemistry
Insulin human is a biosynthetic protein that is structurally identical to endogenous insulin secreted by the beta cells of the human pancreas.1,2,3,5,6,38,53,65,71,75,76 Although structurally identical to endogenous human insulin, commercially available insulin human is not extracted from the human pancreas, but is prepared biosynthetically from cultures of genetically modified Escherichia coli 4,5,6,14,15,38,80 or Saccharomyces cerevisiae .63,65,71,75,76,82,83,84,85,86,89,90
Biosynthetic insulin human (Humulin®) is prepared using recombinant DNA technology and special laboratory strains of nonpathogenic E. coli ; the A and B chains of human insulin are synthesized by different strains of E. coli .4,5,6,14,15,38 The bacteria have been genetically modified by the addition of plasmids that incorporate genes for human insulin synthesis.4,5,6,14,15,38 Biosynthetic insulin human (Novolin® [formerly available as semisynthetic insulin]) is prepared using recombinant DNA technology and strains of Saccharomyces cerevisiae .63,86,88,102 The bacteria have been genetically modified by the addition of plasmids that incorporate genes for human insulin synthesis.63 Unlike the process used for the production of animal insulins (no longer commercially available in the US), the commercial process using recombinant DNA technology to produce insulin human avoids contamination with glucagon, somatostatin, and proinsulin.38,63 Although a possible theoretical source of protein contamination (i.e., E. coli polypeptides [ECPs]) of certain biosynthetic insulin human (i.e., Humulin®) could be derived from the E. coli organism used in its manufacture, this commercially available biosynthetic insulin human contains less than 4 ppm of immunoreactive ECPs.38
Each mg of insulin human has a biologic potency of not less than 27.5 USP insulin human units calculated on a dried basis.60
Insulin (Regular)
Biosynthetic
Biosynthetic insulin human (regular) injection consists of zinc insulin crystals5 that are prepared by precipitating insulin in the presence of zinc chloride.9 Commercially available insulin human (regular) injections containing 100 units/mL are clear and colorless.5,7,71,82,125 Each 100 USP units of biosynthetic insulin human (regular) contains 10-40 mcg of zinc.53,54 However, Novolin® R contains approximately 7 mcg/mL of zinc chloride.63,125 Humulin® R also contains 1.4-1.8% glycerin and 0.225-0.275% cresol54 and has a pH of 7-7.8.54 Novolin® R also contains 16 mg/mL of glycerin and 3 mg/mL of metacresol and has a pH of 7.4.125
Insulin, Isophane
Biosynthetic
Biosynthetic isophane insulin human is an intermediate-acting, sterile suspension of zinc insulin crystals and protamine sulfate in buffered water for injection, combined in a manner such that the solid phase of the suspension consists of crystals composed of insulin, protamine, and zinc.54,75,84 Biosynthetic isophane insulin human suspension is a cloudy or milky suspension6,75,84,90 of rod-shaped crystals free from large aggregates of crystals following moderate agitation.54,63 When examined microscopically, the insoluble material in biosynthetic isophane insulin human suspension (Humulin® N) is crystalline and contains not more than trace amounts of amorphous material.54 Each 100 USP units of biosynthetic isophane insulin human (Humulin® N) contains 10-40 mcg of zinc and 0.15-0.25% dibasic sodium phosphate.54 In addition, it contains 1.4-1.8% glycerin, 0.15-0.175% cresol, and 0.05-0.07% phenol.54 Biosynthetic isophane insulin human (Humulin® N) suspension has a pH of 7.1-7.4.54 Biosynthetic isophane insulin human (Novolin® N) has a pH of 7-7.8 and contains unspecified amounts of zinc, dibasic sodium phosphate, glycerin, cresol, and phenol.63
Stability
Insulin human injections and suspensions should be dispensed in the original, unopened, multiple-dose containers supplied by the manufacturers and have an expiration date of not later than 24-36 months, depending on the specific preparation, after the vial was filled.53,54,55,64 Unopened vials of insulin human injections, prefilled syringes, and suspensions should be stored at 2-8°C and should not be subjected to freezing or exposed to heat and sunlight;5,6,7,8,53,64,65,75,80,82,83,84,88,89,92,93,100,101,115,125 freezing will cause isophane insulin human to resuspend improperly, preventing accurate measurement of a dose.54,55 Unopened solutions and suspensions that have been frozen should be discarded.5,117,119 In addition, agglomeration of particles may occur, altering absorption from the injection site.54,55 The insulin vial in use may be kept at room temperature for up to 1 month;5,6,7,8,65,67,80,82,83,84,88,89,92,93,100,101,114,125 exposure to extremes in temperature (less than 2 °C or greater than 30 °C) or direct sunlight should be avoided.5,6,7,8,65,67,80,82,83,84,88,89,92,93,101,115 Insulin vials in use and stored in the refrigerator may be used beyond 30 days.67 Length of storage of refrigerated insulin vials is dependent on light, agitation, and technique used for dose preparation.67 Warming refrigerated insulin to room temperature prior to use will limit local irritation at the injection site.67,101 Because of possible microbial contamination, a partially empty vial should be discarded if it has not been used for several weeks.5,6,7,8 Insulin human (regular) injection exhibiting discoloration, turbidity, or unusual viscosity should be discarded,5,7,71,82,88,89 since these changes indicate deterioration or contamination.5,7,101 Isophane insulin human suspension alone or in combination with insulin human should be discarded if the suspension is clear and remains clear after the vial is rotated or if the precipitate has become clumped or granular in appearance or has formed a deposit of solid particles on the wall of the vial.6,65,75,76,84,90,93,101,118,120
The individual manufacturer's labeling should be consulted for instructions regarding storage of specific disposable insulin pens or other insulin delivery systems preassembled with cartridges (e.g., Humulin® N Pen, Humulin® 70/30 Pen).117,118,119,120
Infusion bags containing insulin human (regular) are stable at room temperature for 24 hours.125 A certain amount of insulin will initially be adsorbed onto the walls of the infusion bag.125
The compatibility of insulin human (regular) injection with other drugs depends on several factors (e.g., pH of the insulin injection used, concentration of the drugs, specific diluents used, temperature, resulting pH); specialized references should be consulted for specific compatibility information.54,55
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
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