Insulin human is a biosynthetic protein that is structurally identical to endogenous insulin secreted by the beta cells of the human pancreas; commercially available insulin human preparations are classified as short-acting (insulin human [regular]) or intermediate-acting (isophane insulin human).1, 2, 3, 5, 6, 38, 65, 71, 75, 114, 256, 257, 258
Insulin human is used as replacement therapy for the management of diabetes mellitus in pediatric and adult patients, including in the emergency treatment of diabetic ketoacidosis or hyperosmolar hyperglycemic states when rapid control of hyperglycemia is required.5, 6, 65, 71, 75, 113, 258, 259, 260, 261
Insulin human is commercially available as a single entity preparation and also in fixed combination of short- and intermediate-acting insulin.5, 6, 65, 71, 75, 114, 256, 257, 258
Concentrated (U-500) insulin human (regular) is used in patients with marked insulin resistance (daily insulin requirements exceeding 200 units) so that a large dose may be administered subcutaneously in a reasonable volume.256
Insulin human dry powder for inhalation is used in adult patients for the management of diabetes mellitus.257 Insulin human dry powder for inhalation is not recommended for the treatment of diabetic ketoacidosis or in patients who smoke or who have recently stopped smoking.257
Safety and efficacy of insulin human injection have been established during short-term and long-term use.18, 20, 23, 25, 34, 35, 37, 47, 48, 85, 86 Human insulin manufactured using recombinant DNA technology has replaced animal-source insulin (no longer commercially available in the US).101
IV administration of regular insulin provides the greatest flexibility in dosing and is used in preference to subcutaneous administration in hospitalized patients with hyperglycemia (e.g., unrecognized diabetes mellitus, hospital-related hyperglycemia), diabetic ketoacidosis, hyperglycemic hyperosmolar states, poorly controlled diabetes mellitus and widely fluctuating blood glucose concentrations, or severe insulin resistance.113
Insulin human dry powder for inhalation improves glycemic control in both type 1 and type 2 diabetes mellitus as evidenced by reductions in glycosylated hemoglobin (hemoglobin A1c; HbA1c).257, 262, 263
Efficacy of insulin human dry powder for inhalation in combination with basal insulin for the management of type 1 diabetes mellitus in adult patients was established in a 24-week, open-label, active-controlled study in adult patients with inadequately controlled (HbA1C7.5—10%) type 1 diabetes mellitus.257, 262 After completing a 4-week basal insulin optimization period, patients were randomized to receive either insulin human dry powder for inhalation or subcutaneous insulin aspart administered at each meal, in addition to the basal insulin regimen.257 Mealtime insulin doses were titrated to glycemic goals weekly for the first 12 weeks and were kept stable for the last 12 weeks of the study.257, 262 The primary endpoint for the study was change in HbA1c from the end of the basal insulin optimization period to week 24.262 A total of 344 patients were enrolled; baseline demographics and characteristics were similar among treatment groups.262 At week 24, treatment with insulin human dry powder for inhalation in combination with basal insulin was associated with a decrease in HbA1c.257 Insulin human dry powder for inhalation in combination with basal insulin provided less HbA1c reduction than the comparator group (<0.21% versus <0.40%, respectively).257 More patients in the insulin aspart with basal insulin group achieved an HbA1c≤7% compared to patients treated with human insulin dry powder for inhalation with basal insulin (27% versus 14%, respectively).257
Efficacy of insulin human dry powder for inhalation in adult patients with type 2 diabetes mellitus was established in a 24-week, double-blind, placebo-controlled study.257, 263 After a 6-week run-in period, insulin naïve adult patients receiving optimal/maximally controlled dosages of metformin monotherapy or on 2 or more antidiabetic agents with an HbA1c of 7.5—10% were randomized 1:1 to receive either insulin human dry powder for inhalation or placebo dry powder for inhalation.257, 263 Insulin dosages were titrated for the first 12 weeks and were kept stable for the last 12 weeks of the study; dosages of oral antidiabetic agents were kept stable throughout the study period.257 The primary endpoint was change in HbA1c from baseline to week 24.263 A total of 479 patients were enrolled; the median age of enrolled patients was 56.7 years and the baseline demographics and characteristics were similar among treatment groups.257, 263 When used in combination with oral antidiabetic agents, treatment with insulin human dry powder for inhalation resulted in a greater mean reduction in HbA1c than placebo (<0.82% versus <0.42%, respectively).257, 263 A greater number of patients receiving insulin human dry powder for inhalation achieved an HbA1c<7% than the placebo group (32% versus 15%, respectively).257
The American Diabetes Association (ADA) publishes an annual guideline on diabetes management, which provides clinical practice recommendations for glucose-lowering therapies in patients with diabetes mellitus.259 The current 2025 ADA guideline states that in adults with type 2 diabetes mellitus, pharmacologic strategies that provide sufficient effectiveness to achieve and maintain the intended treatment goals should be used and guided by a person-centered, shared decision-making approach.259 In general, higher-efficacy approaches have a greater likelihood of achieving glycemic control.259 Weight management should be included as a distinct treatment goal, and other healthy lifestyle behaviors should also be considered.259 When selecting an appropriate treatment regimen, clinicians should be guided by factors such as cardiovascular and renal comorbidities, drug efficacy and adverse effects, hypoglycemic risk, presence of overweight or obesity, cost, access, and patient preference.259 For the treatment of type 2 diabetes mellitus, insulin should be considered in patients with symptoms of hyperglycemia or when the HbA1c or blood glucose are very high (i.e., HbA1c >10% or blood glucose ≥300 mg/dL).259 Insulin therapy, typically starting with basal insulin, may also be considered in patients on other antidiabetic agents who require additional glycemic control.259 When insulin is used for the treatment of type 2 diabetes mellitus, combination therapy with a glucagon-like peptide-1 (GLP-1) receptor agonist, including a dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist, should be considered for greater glycemic control and for the beneficial effect on weight and hypoglycemia risk.259 For the treatment of type 1 diabetes mellitus, treatment with insulin is essential and should be tailored to the individual patient to meet glycemic goals, prevent diabetic ketoacidosis, and minimize the risk of hypoglycemia.259 Typical insulin treatment plans for patients with type 1 diabetes mellitus include a combination of basal, mealtime, and correction insulin.259 ADA states that insulin should be used in pregnant patients with type 1 diabetes mellitus and is preferred in pregnant patients with type 2 diabetes mellitus and with gestational diabetes mellitus.264 In all patients with diabetes mellitus treated with insulin, routine assessment of administration technique is essential to ensure optimized safety and efficacy.264
The American Association of Clinical Endocrinology (AACE) also publishes guidelines for the management of diabetes mellitus.260, 261 The principles of diabetes management outlined in the guidelines are similar to those recommended by the ADA.261 For patients with type 2 diabetes mellitus, insulin may be used to achieve glycemic control after failure of other antidiabetic agents or in those patients with catabolic symptoms (e.g., weight loss) or high HbA1c or blood glucose values (i.e., HbA1c >10% or blood glucose ≥300 mg/dL).260 Insulin therapy (starting with basal insulin alone or in combination with a GLP-1 receptor agonist) may also be considered in patients on other antidiabetic agents (including a GLP-1 receptor agonist) who require additional glycemic control.260 Insulin is recommended for the treatment of all patients with type 1 diabetes mellitus.261
The ADA also publishes guidelines on the management of hyperglycemic crises, including diabetic ketoacidosis (DKA) and hyperglycemic hyperosmolar state (HHS).113 These guidelines recommend that insulin be started as soon as possible after a diagnosis of DKA, preferably as a continuous IV infusion of short-acting insulin.113 In patients with uncomplicated mild or moderate DKA, treatment with subcutaneous rapid-acting insulin analogs may be considered.113 Subcutaneous rapid-acting insulin is not recommended for patients with severe and complicated DKA or with HHS.113 In patients with DKA not previously prescribed insulin, an insulin regimen consisting of basal and prandial insulin should be started after the resolution of DKA.113 In patients with HHS, insulin administered by continuous IV infusion should be started and directed by the presence (or absence) and degree of ketonemia and acidosis; continuous IV infusion may be used concomitantly with basal insulin in those patients already receiving it.113
While insulin human (regular) has been used in combination with IV potassium chloride and dextrose (d-glucose) (referred to as glucose-insulin-potassium or GIK therapy) early in the course of suspected acute ST-segment-elevation myocardial infarction† (STEMI) for metabolic modulation and potential beneficial effects on morbidity and mortality,96, 97, 98, 99 data from a large randomized trial suggest that high-dose GIK therapy is not beneficial in reducing mortality following acute STEMI. Further evaluations have found that this therapy may be harmful and GIK therapy is no longer recommended.95, 265
IV insulin human (often in combination with glucose to prevent hypoglycemia), is used to shift potassium intracellularly in themanagement of hyperkalemic emergencies when urgent reduction in serum potassium levels is needed†.266
-Adrenergic or Calcium Channel Blocking Agent Overdosage
High-dose insulin euglycemic therapy (HIET), utilizing IV insulin human (regular) at 1—10 units/kg per hour following an initial loading dose of 1 unit/kg in combination with glucose, is used in the setting of hemodynamic instability (hypotension, shock) associated with β-adrenergic or calcium channel blocking agent overdose† in patients refractory to other treatments.267, 268, 269 In this setting, HIET is a positive inotrope and increases cardiac output and blood pressure.268 Resuscitation following cardiac arrest from β-adrenergic or calcium channel blocking agent overdosage should follow standard basic life support (BLS) and advanced cardiac life support (ACLS) algorithms.269 While no controlled studies have been conducted, available evidence from animal studies, case series, and case reports indicate that HIET can increase heart rate and improve hemodynamics and can be considered in those patients who are in refractory shock.269
Dispensing and Administration Precautions
Oral Inhalation via Dry Powder Inhaler
Insulin human dry powder for oral inhalation is supplied in single-use cartridges that are administered using a drug-specific inhaler device.257 A single inhaler should be used at a time; the same inhaler can be used for all dosages.257 The cartridges should not be opened; the inhaler device opens the cartridge automatically during use.257 Prior to use, the cartridge should be at room temperature for 10 minutes and the correct dose of cartridge should be verified.257 For dosages exceeding the contents of a single cartridge, inhalations from more than one cartridge may be necessary.257 Insulin human dry powder for inhalation should be administered at the beginning of each meal.257 The inhaler should be kept level with the white mouthpiece on top and purple base on the bottom after a cartridge has been inserted into the inhaler.257 Loss of effect can occur if the inhaler is turned upside down, held with the mouthpiece pointing down, shaken, or dropped after the cartridge has been inserted but before the dose has been administered; if any of the above occurs, replace the cartridge before use.257 After use, the inhaler should be stored in a clean, dry place with the mouthpiece cover on until the next dose is due.257 See full prescribing information for additional details on administration, including administration technique.257
When not in use, insulin human dry powder for inhalation should be stored refrigerated at 2—8°C.257 Sealed, unopened foil packages may be stored under refrigeration (at 2—8°C) until the expiration date.257 Sealed, unopened blister cards and strips stored at 2—8°C must be used within 1 month.257 If a foil package, blister card, or strip is not refrigerated, the contents must be used within 10 days.257 When in use, sealed, unopened blister cards and strips may be stored at room temperature up to 25°C but must be used within 10 days.257 Open strips stored at room temperature up to 25°C must be used within 3 days.257 A blister card or strip stored at room temperature should not be returned to the refrigerator.257 The inhaler can be stored refrigerated or at room temperature; if refrigerated, the inhaler should be at room temperature before use.257 The inhaler can be used for up to 15 days from the date of first use; after 15 days, the inhaler must be discarded and replaced with a new inhaler.257
Insulin human (regular) should be clear and colorless and should not be used if it appears cloudy, thick, slightly colored, or contains particulate matter.5, 71, 256
Insulin human (regular) injection is usually administered by subcutaneous injection 30 minutes before meals into the thigh, upper arm, abdomen, or buttocks.5, 71, 256 Most individuals should grasp a fold of skin lightly with the fingers at least 3 inches apart and inset the needle at a 90° angle; thin individuals or children may need to pinch the skin and insert at a 45° angle to avoid IM injection, especially in the thigh area.101 Injection sites should be rotated within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis.5, 71, 101, 256 Areas with lipodystrophy or localized cutaneous amyloidosis should not be used.5, 71 The label should be checked prior to administration to ensure the correct insulin product has been selected.5, 71, 256 Excessive agitation of the vial prior to withdrawing the insulin dose should be avoided since loss of potency, clumping, frosting, or precipitation may occur.101 Warming refrigerated insulin to room temperature prior to use will limit local irritation at the injection site.101 See full prescribing information for additional details on administration, including administration technique.5, 71
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.71
Unopened vials of insulin human (regular) U-100 and U-500 can be stored at 2—8°C until the expiration date.5, 71, 256 Unopened vials of insulin human U-100 can be stored at room temperature (up to 25°C) for 31 (Humulin® R) or 42 days (Novolin® R).5, 71 Opened (in-use) vials of insulin human U-100 can be stored refrigerated (2—8°C) or at room temperature for 31 days (up to 30°C for Humulin® R) or 42 days (up to 25°C for Novolin® R).5, 71 Unopened insulin human pens (Novolin® R FlexPen®) can be stored at 2—8°C until the expiration date.71 Unopened insulin human pens (Novolin® R FlexPen®) can be stored at room temperature (up to 30°C) for 28 days.71 Opened (in-use) insulin human pens (Novolin® R FlexPen®) can be stored refrigerated (2—8°C) or at room temperature (up to 30°C) for 28 days.71
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.256 The manufacturer further warns that serious consequences may result if this concentrated injection were used other than under constant medical supervision.256 Concentrated insulin human (U-500) should be administered using only U-500 insulin syringes.256 To minimize the risk of hypoglycemia, do not administer insulin U-500 intravenously or in an insulin pump or mix with any other insulin products or solutions.256 Unopened vials of insulin human U-500 can be stored at room temperature (up to 30°C) for 40 days.256 Opened (in-use) vials of insulin human U-500 can be stored refrigerated (2—8°C) or at room temperature (up to 30°C) for 40 days.256 Unopened concentrated (U-500) insulin human pens can be stored at room temperature (up to 30°C) for 28 days.256 Opened (in-use) concentrated insulin human pens (U-500) should not be refrigerated but can be stored at room temperature (up to 30°C) for up to 28 days.256
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; such routes of administration are not recommended for routine use.101, 113, 258, 259 For IV infusion, the manufacturer of Novolin® R insulin human (regular) injection states that the injection is diluted to a concentration of 0.05-1 unit/mL; Novolin® R is stable in 0.9% sodium chloride, 5% dextrose, or 10% dextrose injection with 40 mEq/L of potassium chloride in polypropylene infusion bags for up to 24 hours at room temperature.71 For IV infusion, the manufacturer of Humulin® R insulin human (regular) injection states that the injection is diluted to a concentration of 0.1-1 unit/mL in 0.9% sodium chloride; after dilution, the drug is stable for up to 48 hours when stored in the refrigerator (2—8°C) and then may be used at room temperature for up to an additional 48 hours.5 Insulin human regular U-500 should not be administered IV.256 Commercially available IV infusion bags of insulin human (regular) (Myxredlin®) must be stored in the refrigerator (2—8°C) in the original container protected from light.258 If needed, the infusion bag can be removed from the original carton and stored at room temperature (up to 25°C) for up to 30 days; once removed from refrigeration, the product should not be returned to refrigeration.258 Commercially available IV infusion bags of insulin human should not be used if frozen and should not be shaken.258
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].
Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
Adults | 1 unit/mL | units/hour or units/kg/houra |
16 units/mL for calcium channel blocker/beta-blocker overdose | ||
Pediatric patients (<50 kg) | 0.2 units/mL | units/kg/hour |
1 unit/mL |
Diabetic ketoacidosis protocols may require units/kg/hour
Isophane insulin human suspension is usually administered subcutaneously into the abdominal wall, thigh, upper arm, or buttocks;6, 75 this form of insulin must not be administered IV.6, 75 Injection sites should be rotated within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis.6, 75 Areas with lipodystrophy or localized cutaneous amyloidosis should not be used.6, 75 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, 65, 75 This may be done by slowly rotating and inverting or carefully shaking the vial several times before withdrawal of each dose.6, 75 Vigorous shaking should be avoided since this causes frothing, which interferes with correct measurement of a dose.6, 75 See full prescribing information for additional details on administration, including administration technique.6, 75
Fixed combinations containing isophane insulin human suspension and insulin human (regular) injection are administered by sub-Q injection.65, 114
When a compatible delivery device is used for subcutaneous injection of isophane insulin human suspension (e.g., Humulin® N KwikPen®, Novolin® N FlexPen®) or the fixed combination containing insulin human (regular) injection and isophane insulin human suspension (e.g., Humulin® 70/30 KwikPen®, Novolin® 70/30 FlexPen®), the accompanying labeling should be consulted for proper methods of assembly, administration, and care.65, 117, 119
Isophane insulin human should not be used in an insulin infusion pump.6, 75
Store unopened vials of isophane insulin human in the refrigerator (at 2—8°C) until the expiration date.6, 75 Unopened vials of isophane insulin human may be stored at room temperature for 31 days (up to 30°C for Humulin® N) or 42 days (up to 25°C for Novolin® N).6, 75 Opened (in-use) vials of isophane insulin human (Humulin®N) can be stored refrigerated (2—8°C) or at room temperature (up to 30°C) for 31 days.6 Opened (in-use) vials of isophane insulin human (Novolin® N) can be stored at room temperature (up to 25°C) for 42 days; the manufacturer states that opened vials should not be refrigerated.75 Unopened isophane insulin human pens can be stored in the refrigerator (at 2—8°C) until the expiration date.6, 75 Unopened isophane insulin human pens can be stored at room temperature for 14 days (up to 30°C for Humulin® N KwikPen®) or 28 days (up to 30°C for Novolin® N FlexPen®).6, 75 Opened (in-use) isophane insulin human pens should not be refrigerated but can be stored at room temperature up to 30°C for 14 days (Humulin®N KwikPen®) or 28 days (Novolin® N FlexPen®).6, 75
Dosage of insulin human is always expressed in USP units.5, 6, 65, 71, 75, 114, 256, 258
Dosage of insulin should be individualized based on the route of administration, the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal to attain optimum therapeutic effect.5, 6, 65, 71, 75, 114, 256, 257, 258 Dosage modifications may be needed with changes in physical activity, changes in meal patterns (e.g., macronutrient content, timing of food intake), changes in renal or hepatic function, or during acute illness.5, 6, 65, 114, 256, 257, 258
Any change in insulin preparation or dosage regimen should be made with caution and only under medical supervision.5, 6, 65, 71, 75, 114, 256, 257 Changes in strength, brand, type, and/or method of manufacture may necessitate a change in dosage.5, 6, 65, 71, 75, 114, 256, 257, 258
In adult patients naïve to insulin therapy, the recommended initial dosage of insulin human dry powder for inhalation is 4 units at the beginning of each meal.257
In adult patients currently using subcutaneous prandial (mealtime) insulin, the recommended initial dosage of insulin human dry powder for inhalation is based on the current injected mealtime insulin dosage (Table 2).257
In adult patients currently using subcutaneous, pre-mixed insulin, the initial recommended dosage of insulin human dry powder for inhalation is determined by first estimating the current mealtime insulin dosage injected.257 The mealtime dosage is estimated by dividing one-half of the total daily pre-mixed insulin dosage equally among the three meals of the day.257 Each estimated injected mealtime dosage is then converted to an appropriate insulin human dry powder for inhalation dosage using Table 2.257 The remaining one-half of the total daily pre-mixed insulin dosage should be administered as basal insulin.257
Injected Mealtime Insulin Dosage | Insulin Human Dry Powder for Inhalation Dosage |
|---|---|
Up to 4 units | 4 units |
5—8 units | 8 units |
9—12 units | 12 units |
13—16 units | 16 units |
17—20 units | 20 units |
21—24 units | 24 units |
For insulin human dry powder for inhalation dosages exceeding the contents of a single cartridge at mealtime, inhalation from more than one cartridge are necessary.257 To achieve the required total mealtime dosage, a combination of 4 unit, 8 unit, and 12 unit cartridges may be used.257
When switching from another insulin to insulin human dry powder for inhalation, a different insulin dosage may be needed, requiring increased frequency of blood glucose monitoring.257
Initial total daily insulin dosages in adults and pediatric patients with type 1 diabetes mellitus range from 0.4—1 unit/kg.259 Starting dosages may be higher, particularly after a new diagnosis or during puberty, menses, or medical illness, or lower (i.e., 0.2—0.6 units/kg per day), particularly in young children or those in partial remission.259 In metabolically stable adults with type 1 diabetes mellitus, 0.5 units/kg per day is used as a typical starting dosage, with approximately one-half administered as prandial insulin and one-half given as basal insulin.259 Typical treatment plans for patients with type 1 diabetes mellitus include a combination of prandial and long-acting insulin.259
In patients with type 2 diabetes mellitus, when adding prandial insulin, the initial dosage is a single dose of 4 units or 10% of the basal insulin dosage administered with the largest meal of the day.259 Alternatively, in patients with type 2 diabetes mellitus being treated with basal insulin who require addition of prandial insulin, the regimen can be converted to two doses of pre-mixed insulin.259 In general, the total daily insulin dosage in patients with type 2 diabetes mellitus is 1 unit/kg per day.259
Insulin human (regular) should be administered prior to a meal.259 Insulin human (regular) should generally be used in regimens that include an intermediate- or long-acting insulin.5, 71
Isophane insulin human should be administered subcutaneously once or twice daily.75 In patients with type 1 diabetes mellitus, isophane insulin human should generally be used in combination with a short-acting insulin.75
Isophane insulin human in fixed combination with insulin human is typically administered twice daily and should be injected subcutaneously approximately 30—45 minutes before a meal.65, 114
Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State
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 state.113 Prompt correction of hyperglycemia with adequate doses of insulin, correction of dehydration and electrolyte imbalances with IV fluid (with 0.9% sodium chloride solution or other crystalloid solution) and electrolyte therapy, and frequent monitoring of clinical and laboratory data are essential to successful treatment of these hyperglycemic crises.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
For the treatment of moderate to severe diabetic ketoacidosis (plasma glucose exceeding 200 mg/dL with arterial pH of 7-7.25 or less and serum bicarbonate of 10-15 mEq/L or less) in adults, the American Diabetes Association (ADA) recommends a loading dose of 0.1 units/kg of regular insulin by direct IV injection, followed by continuous IV infusion of 0.1 units/kg per hour.113 In patients with hyperosmolar hyperglycemia, the ADA recommends a continuous IV infusion of 0.05 units/kg per hour of regular insulin.113 When a plasma glucose concentration of <250 mg/dL is achieved, the insulin infusion rate may be decreased to 0.05 units/kg per hour.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., serum glucose <250 mg/dL, serum osmolality of 300 mOsm/kg or less, and urine output >0.5 mL/kg per hour).113
For the treatment of mild diabetic ketoacidosis (plasma glucose exceeding 200 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 While the IM route is effective, it is more painful than the subcutaneous route and may increase the risk of bleeding in patients receiving anticoagulants.113 A loading dose of regular insulin 0.1 units/kg should be given.113 After the loading dose, 0.1 units/kg every hour or 0.2 units/kg every 2 hours of regular insulin may be given subcutaneously until the blood glucose is <250 mg/dL†.113 When the target glucose concentration has been achieved, the insulin dosage should be decreased to 0.1 units/kg every 2 hours subcutaneously until resolution.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.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 or recurrence of ketoacidosis.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 or insulin-naïve patients should receive a total insulin dosage of 0.5-0.6 units/kg daily as part of a multiple-dose regimen of short- and long-acting insulin until an optimal dosage is established.113 Patients with risk factors for hypoglycemia (e.g., renal failure, frailty) may receive 0.3 units/kg daily.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
In pediatric patients with diabetic ketoacidosis, treatment guidelines recommend initiation of insulin therapy with an IV infusion of regular insulin at a rate of 0.05—0.1 units/kg per hour after initial fluid resuscitation in volume depleted patients; an initial direct IV injection of insulin is not recommended in pediatric patients.272 A lower starting dosage of 0.05 units/kg per hour (or 0.03 units/kg per hour in patients <5 years of age) can be considered in those patients with a pH >7.15.272 If IV access is unavailable or for uncomplicated mild or moderate diabetic ketoacidosis, insulin may be given subcutaneously or IM.272 The recommended dosage of subcutaneous insulin is 0.15 units/kg every 2 hours, initiated 1 hour after fluid replacement.272 In mild diabetic ketoacidosis, the recommended dosage of subcutaneous insulin is 0.13—0.17 units/kg per dose every 4 hours; the dosage can be increased or decreased by 10—20% based on blood glucose levels and dosing frequency may be increased to every 2 or 3 hours if acidosis is not improving.272 Glucose should be added to IV fluids when the serum blood glucose is ≤300 mg/dL.272 IV insulin should be continued until resolution of diabetic ketoacidosis (pH >7.3, serum bicarbonate >18 mEq/L, or closure of the anion gap).272 Serum electrolyte, glucose concentrations, and venous pH should be determined every 2 hours until the patient is stable.272
After diabetic ketoacidosis in pediatric patients has resolved and oral intake is tolerated, subcutaneous insulin may be initiated using a combination of rapid- or short-acting insulin in addition to basal insulin according to standard recommendations in treatment guidelines.272 An overlap of 15—30 minutes between IV and rapid-acting subcutaneous insulin should occur before stopping the IV insulin infusion to prevent rebound hyperglycemia.272
In pediatric patients with hyperosmolar hyperglycemia, insulin therapy with an IV infusion of regular insulin at a rate of 0.025—0.05 units/kg per hour should be initiated when blood glucose no longer decreases with administration of fluids alone.272 The dosage of insulin should be titrated to decrease blood glucose by 50—75 mg/dL per hour.272
The manufacturers of insulin human make no specific dosage recommendations for patients with hepatic impairment.5, 6, 65, 71, 114, 256, 257, 258 Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and more frequent blood glucose monitoring.5, 6, 65, 71, 114, 256, 257, 258
The manufacturers of insulin human make no specific dosage recommendations for patients with renal impairment.5, 6, 65, 71, 114, 256, 257, 258 Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and more frequent blood glucose monitoring.5, 6, 65, 71, 114, 256, 257, 258
The manufacturers of insulin human make no specific dosage recommendations for geriatric patients.5, 6, 65, 71, 75, 114, 257, 258 Elderly patients may be at increased risk of hypoglycemia due to co-morbid disease states and concomitant medications.5, 6, 65, 71, 75, 114, 257, 258
Caution should be exercised with using insulin human regular U-500 in geriatric patients; the initial dosage, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemia.256
Bronchospasm in Patients with Chronic Lung Disease
A boxed warning is included in the prescribing information of insulin human dry powder for inhalation concerning the increased risk of acute bronchospasm in patients with chronic lung disease.257 Acute bronchospasm has been observed in patients treated with insulin human dry powder for inhalation.257 In a study of patients with asthma whose bronchodilators were temporarily withheld for assessment, bronchoconstriction and wheezing following insulin human dry powder for inhalation administration was reported in 29% (5 of 17) and 0% of patients with and without a diagnosis of asthma, respectively.257 In this study, a mean decline in forced expiratory volume in 1 second (FEV1) of 400 mL was observed 15 minutes after a single dose in patients with asthma.257 In a subset study of 8 patients with COPD, a mean decline in FEV1 of 200 mL was observed 18 minutes after a single dose.257
Because of the risk of acute bronchospasm, insulin human dry powder for inhalation is contraindicated in patients with chronic lung disease such as asthma or COPD.257 Before initiating therapy with insulin human dry powder for inhalation, evaluate all patients with a detailed medical history, physical examination, and spirometry (FEV1) to identify potential underlying lung disease.257
Other Warnings and Precautions
Sharing of Injection Pens, Syringes, or Needles
Injection pens containing insulin human products should never be shared with another person, even if the needle is changed.5, 6, 65, 71, 75, 114, 256 Syringes and needles used with insulin human vials also should not be shared with another person.5, 6, 65, 71, 75, 114, 256 Sharing poses a risk of transmission of blood-borne pathogens.5, 6, 65, 71, 75, 114, 256
Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia.5, 6, 71, 114, 256, 257, 258 Any changes to a patient's insulin regimen should be performed under close medical supervision with increased frequency of blood glucose monitoring.5, 6, 65, 71, 75, 114, 256, 257 For patients with type 2 diabetes mellitus, adjustments in concomitant antidiabetic agents may be needed.5, 6, 65, 71, 114, 256, 257
Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia.5, 6, 65, 71, 75, 114, 256 Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and monitor for hypoglycemia.5, 6, 65, 71, 75, 114, 256
Hypoglycemia is the most common adverse reaction of all insulins, including insulin human.5, 6, 65, 71, 75, 114, 256, 257, 258 Severe hypoglycemia may cause seizures, lead to unconsciousness, may be life threatening, or cause death.5, 6, 65, 71, 75, 114, 256, 257, 258 Hypoglycemia may impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).5, 6, 65, 71, 75, 114, 256, 257
Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient.5, 6, 65, 71, 75, 114, 256, 257, 258 The risk of hypoglycemia after injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal.5, 6, 65, 71, 75, 114 As with all insulins, the glucose lowering effect time course of insulin human may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature.5, 6, 65, 71, 114
Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes mellitus, in patients with diabetic neuropathy, in patients using medications that block the sympathetic nervous system (e.g., β-adrenergic blocking agents), or in patients who experience recurrent hypoglycemia.5, 6, 65, 71, 75, 114, 256, 257, 258 Factors that may increase the risk of hypoglycemia include changes in nutrition (e.g., changes in macronutrient content or timing of meals), level of physical activity, and concurrent medications.5, 6, 65, 71, 75, 114, 256, 257, 258 Patients with renal or hepatic impairment may be at higher risk of hypoglycemia.5, 6, 65, 71, 75, 114, 256, 257, 258 To minimize the risk of hypoglycemia, do not administer insulin regular U-500 intravenously or in an insulin pump or mix with any other insulin products or solutions.256
Patients and caregivers must be educated to recognize hypoglycemia.5, 6, 65, 71, 75, 114, 256, 257, 258 Self-monitoring of blood glucose is essential in the prevention and management of hypoglycemia.5, 6, 65, 71, 75, 114, 256, 257 In patients at higher risk of hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.5, 6, 65, 71, 75, 114, 256, 257, 258
Accidental mix-ups between insulin products have been reported.5, 6, 65, 71, 75, 114 To avoid medication errors between insulin human and other insulins, instruct patients to always check the label before each injection.5, 6, 65, 71, 75, 114 Insulin human regular U-500 should be administered using only a U-500 insulin syringe to avoid administration errors; no other syringe should be used.256
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin human.5, 6, 65, 71, 75, 114, 256, 257, 258 Generalized allergy to insulin may manifest as a whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.65, 75, 258 If hypersensitivity occurs, discontinue insulin human; treat according to the standard of care and monitor until signs and symptoms resolve.5, 6, 65, 71, 75, 114, 256, 257, 258 Insulin human is contraindicated in patients who have had a hypersensitivity reaction to insulin human or its excipients.5, 6, 65, 71, 75, 114, 256, 257, 258
All insulins, including insulin human, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia.5, 6, 65, 71, 75, 114, 256, 257, 258 Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmias, and death.5, 6, 65, 71, 75, 114, 256, 257, 258
Monitor potassium levels in patients at risk for hypokalemia (e.g., patients taking potassium-lowering medications or medications sensitive to serum potassium concentrations).5, 65, 71, 75, 114, 256, 257, 258
Fluid Retention and Heart Failure
Peroxisome proliferator-activated receptor (PPAR)-γ agonists (i.e., thiazolidinediones) can cause dosage-related fluid retention when used in combination with insulin.5, 6, 65, 71, 75, 114, 256, 257, 258 Fluid retention may lead to or exacerbate heart failure.5, 6, 65, 71, 75, 114, 256, 257, 258
Patients treated with insulin, including insulin human, and a PPAR-γ agonist should be observed for signs and symptoms of heart failure.5, 6, 65, 71, 75, 114, 256, 257, 258 If heart failure develops, it should be managed according to the current standards of care, and discontinuation or dosage reduction of the PPAR-γ agonist must be considered.5, 6, 65, 71, 75, 114, 256, 257, 258
Insulin human dry powder for inhalation causes a decline in pulmonary function over time as measured by forced expiratory volume in 1 second (FEV1).257 In clinical trials excluding patients with chronic lung disease and lasting up to 2 years, insulin human dry powder for inhalation-treated patients experienced a small but greater FEV1 decline than comparator-treated patients.257 The FEV1 decline was noted within the first 3 months, and persisted for the entire duration of therapy (up to 2 years).257 The annual rate of FEV1 decline did not appear to worsen with increased duration of use.257 The effects of insulin human dry powder for inhalation on pulmonary function with treatment durations greater than 2 years have not been established.257 There are insufficient data in long term studies to draw conclusions regarding the reversal of the effect on FEV1 after discontinuation of insulin human dry powder for inhalation.257
Assess pulmonary function (e.g., spirometry) at baseline, after the first 6 months of therapy, and annually thereafter, even in the absence of pulmonary symptoms.257 In patients who have a decline of ≥20% in FEV1 from baseline, consider discontinuing insulin human dry powder for inhalation.257 Consider more frequent monitoring of pulmonary function in patients with symptoms such as wheezing, bronchospasm, breathing difficulties, or persistent or recurring cough.257 If symptoms persist, discontinue insulin human dry powder for inhalation.257
In clinical trials, two cases of lung cancer (one in controlled trials and one in uncontrolled trials totaling 2750 patient-years of exposure) were observed in patients exposed to insulin human dry powder for inhalation compared to no cases in patients exposed to comparators (representing 2169 patient-years of exposure).257 In both cases, a prior history of heavy tobacco use was identified as a risk factor for lung cancer.257 Two additional cases of lung cancer (squamous cell and lung blastoma) occurred in nonsmokers exposed to insulin human dry powder for inhalation and were reported by investigators after clinical trial completion.257 These data are insufficient to determine whether insulin human dry powder for inhalation has an effect on lung or respiratory tract tumors.257
In patients with active lung cancer, those with a prior history of lung cancer, or in patients at risk for lung cancer, consider whether the benefits of insulin human dry powder for inhalation use outweigh this potential risk.257
In clinical trials enrolling patients with type 1 diabetes mellitus, diabetic ketoacidosis (DKA) was more common in patients receiving insulin human dry powder for inhalation (0.43%) than comparator-treated patients (0.14%).257
Patients with type 1 diabetes mellitus should always use insulin human dry powder for inhalation in combination with basal insulin.257
In patients at risk for DKA, such as those with acute illness or infection, increase the frequency of glucose monitoring and consider discontinuing insulin human dry powder for inhalation and giving insulin using an alternate route of administration.257
Several studies have shown parenteral insulin human to be less immunogenic than purified pork insulin (no longer commercially available in the US).34, 35, 45, 46, 59 Data from several studies in patients with diabetes mellitus have shown that insulin antibodies (IgE type) develop less frequently following administration of insulin human than following purified animal insulins (no longer commercially available in the US).35, 46 Although a few patients in these studies developed elevated insulin antibody titers (IgE type) following administration of insulin human, they did not develop any signs or symptoms of insulin allergy or adverse reactions to insulin human.35, 46 In one study in patients with diabetes mellitus who had not previously received insulin therapy, insulin human was associated with relatively weaker immunogenicity than purified pork insulin as determined by fasting insulin antibody levels.59
As with all therapeutic proteins, administration of insulin human may cause anti-insulin antibodies to form.5, 65, 71, 75, 256, 257, 258 Development of antibodies that react with human insulin have been observed with all insulins, including insulin human.6, 114 Increases in anti-insulin antibodies were observed more frequently in patients treated with insulin human dry powder for inhalation than in patients treated with subcutaneously injected mealtime insulin; there was no significant effect of anti-drug antibodies on safety or effectiveness over the treatment duration of studies of insulin human dry powder for inhalation that spanned 3 to 24 months.257
Insulin human is contraindicated in patients who are hypersensitive to insulin human or to any ingredient in the formulation.5, 6, 65, 71, 75, 114, 256, 257, 258
While available studies cannot definitely establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with insulin human injection use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes.5, 6, 65, 71, 75, 114, 256, 258 There is limited available data on the use of insulin human dry powder for inhalation in pregnant women; data are insufficient to determine drug-associated risks for adverse developmental outcomes.257 All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.5, 6, 65, 71, 75, 114, 256, 257, 258
Animal reproduction studies have not been performed with insulin human for injection.5, 6, 65, 71, 75, 114, 256, 257 In animal reproduction studies with insulin human dry powder for inhalation, there were no adverse developmental outcomes with subcutaneous administration of carrier particles (vehicle without insulin) to pregnant rats during organogenesis at doses 21 times the human exposure at a daily dose of 99 mg, based on AUC.257
There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy.5, 6, 65, 71, 75, 114, 256, 257, 258 Poorly controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.5, 6, 65, 71, 75, 114, 256, 257, 258 Poorly controlled diabetes mellitus in pregnancy increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.5, 6, 65, 71, 75, 114, 256, 257, 258
Available data from published literature suggests that exogenously administered human insulin is distributed into human milk.5, 6, 65, 71, 75, 114, 256, 258 There are no adverse effects reported in breast-fed infants in the literature.5, 6, 65, 71, 75, 114, 256, 258 There are no data on the effects of exogenous human insulin products on milk production.5, 6, 65, 71, 75, 114, 256, 258
There are no data on the presence of insulin human dry powder for inhalation in human milk, the effects on the breast-fed infant, or the effects on milk production; carrier particles administered subcutaneously are present in rat milk at approximately 10% of the maternal exposure.257 Based on the results of the rat study, it is highly likely that both insulin human and the carrier particles are distributed into human milk.257 Potential adverse effects that are related to inhalation administration of insulin human are unlikely to be associated with potential exposure through breast milk.257
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for insulin human and any potential adverse effects on the breast-fed child from insulin human or the underlying maternal condition.5, 6, 65, 71, 75, 114, 256, 257, 258
Most commercially available insulin human products are indicated to improve glycemic control in pediatric patients with diabetes mellitus.5, 6, 65, 71, 75, 258 The dosage of insulin human must be individualized in pediatric patients based on metabolic needs and frequent monitoring of blood glucose to minimize the risk of hypoglycemia.5, 6, 65, 71, 75, 258 Safety and effectiveness of insulin human regular U-500 in pediatric patients requiring more than 200 units of insulin per day for glycemic control have been established; use is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus.256 Although Novolin® 70/30 insulin isophane human-insulin human mixture injectable suspension is labeled for use in pediatric patients with diabetes mellitus, the manufacturer of Humulin® 70/30 isophane insulin human-insulin human mixture injectable suspension states that the safety and effectiveness of Humulin® 70/30 have not been established in pediatric patients.114 Safety and effectiveness of insulin human dry powder for inhalation have not been established in pediatric patients.257
The effect of age on the pharmacokinetics and pharmacodynamics of insulin human has not been established.5, 6, 65, 71, 75, 114, 257, 258 Elderly patients may be at increased risk of hypoglycemia due to co-morbid disease states and concomitant medications.5, 6, 65, 71, 75, 114, 258 Caution should be exercised with using insulin human regular U-500 in geriatric patients; in geriatric patients, the initial dosage, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.256
In clinical trials, 18 of 1285 patients (1.4%) with type 1 diabetes mellitus and 151 of 635 patients (24%) with type 2 diabetes mellitus treated with insulin human (Novolin® R) were ≥65 years of age.71 Conclusions are limited regarding the efficacy and safety in patients ≥65 years of age.71
In clinical trials with insulin human dry powder for inhalation, 671 patients (12%) were ≥65 years of age, of which 42 (0.8%) were ≥75 years of age.257 In these studies, 381 (13%) of insulin human dry powder for inhalation-treated patients were ≥65 years of age, of which 20 (0.7%) were ≥75 years of age.257 No overall differences in effectiveness with insulin human dry powder for inhalation have been observed between patients ≥65 years of age and younger adult patients.257 Clinical studies with insulin human dry powder for inhalation did not include sufficient numbers of patients 65 years of age and older to determine whether there were differences in safety between these and younger patients.257
The effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of insulin human has not been studied.5, 6, 65, 71, 75, 114, 257, 258 Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and more frequent blood glucose monitoring.5, 6, 65, 71, 75, 114, 256, 257, 258
The effect of renal impairment on the pharmacokinetics and pharmacodynamics of insulin human has not been studied.5, 6, 65, 71, 75, 114, 257, 258 Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure.257 Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent dosage adjustment and more frequent blood glucose monitoring.5, 6, 65, 71, 114, 256, 257, 258
The most common adverse reactions observed with insulin human (regular) include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash.5, 71, 256, 258
The most common adverse reactions observed with isophane insulin human include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight gain, and edema.6, 75
The most common adverse reactions observed with isophane insulin human in fixed combination with insulin human include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, weight gain and edema.65, 114
The most common adverse reactions associated with insulin human dry powder for inhalation (≥2% of patients) include hypoglycemia, cough, and throat pain or irritation.257
Drugs That May Potentiate Hypoglycemic Effects
Interactions are possible with drugs that may potentiate the hypoglycemic effects of insulin human products (e.g., angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, antidiabetic agents, disopyramide, fibrate derivatives, fluoxetine, monoamine oxidase [MAO] inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin derivatives [e.g., octreotide], sulfonamide anti-infectives).5, 6, 65, 71, 75, 114, 256, 257, 258 Dosage adjustments and increased frequency of glucose monitoring may be required if insulin human is used concomitantly with these drugs.5, 6, 65, 71, 75, 114, 256, 257, 258
Albuterol increases the AUC of insulin human dry powder for inhalation by 25%.257
Drugs That May Antagonize Hypoglycemic Effects
Interactions are possible with drugs that may antagonize the hypoglycemic effects of insulin human products, such as atypical antipsychotics (e.g., olanzapine, clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, progestins (e.g., oral contraceptives), phenothiazines, protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.5, 6, 65, 71, 75, 114, 256, 257, 258 Dosage adjustments and increased frequency of glucose monitoring may be required if an insulin human product is used concomitantly with these drugs.5, 6, 65, 71, 75, 114, 256, 257, 258
Drugs That May Have a Variable Effect of Glycemic Control
Interactions are possible with drugs that may have a variable effect on glycemic control (e.g., alcohol, β-adrenergic blocking agents, clonidine, lithium salts, pentamidine).5, 6, 65, 71, 75, 114, 256, 257, 258 Dosage adjustments and increased frequency of glucose monitoring may be required if an insulin human product is used concomitantly with these drugs.5, 6, 65, 71, 75, 114, 256, 257, 258
Drugs That May Reduce of Eliminate Signs of Hypoglycemia (Sympatholytic Agents)
Sympatholytic agents (e.g., β-adrenergic blocking agents, clonidine, guanethidine, reserpine) may decrease or eliminate the signs of hypoglycemia.5, 6, 65, 71, 75, 114, 256, 257, 258 Increased frequency of glucose monitoring may be required when an insulin human product is used concomitantly with these drugs.5, 6, 65, 71, 75, 114, 256, 257, 258
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 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 or Saccharomyces cerevisiae .85, 86 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 .86 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 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 Insulin human lowers blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting glucose production.5, 6, 65, 71, 75, 114, 256, 257, 258 Insulin human also inhibits lipolysis and proteolysis and enhances protein synthesis.5, 6, 65, 71, 75, 114, 256, 257, 258
After subcutaneous injection of insulin human (regular), the pharmacologic effect begins approximately 30 minutes (range: 10—75 minutes) after administration,5, 71 The onset of action is more rapid when administered IV (approximately 10—15 minutes).5, 71 In healthy subjects given subcutaneous insulin regular, peak insulin concentrations occurred between 36—150 minutes (Humulin® R) and 1.5—2.5 hours (Novolin® R) after dosing.5, 71 The peak insulin level of concentrated (U-500) insulin human regular occurs between 4—8 hours (range: 0.5—8 hours) after subcutaneous administration in healthy obese individuals.256 After subcutaneous administration of isophane insulin human, the median peak serum concentration occurred at approximately 4 hours (range: 1—12 hours).6 After oral inhalation of insulin human, the time to maximum serum insulin concentrations ranged from 10—20 minutes.257 The absolute bioavailability of insulin human (regular) ranges from 48—89% after subcutaneous injection.5 Uptake and degradation of insulin human predominantly occurs in the liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in clearance of insulin.5, 6, 256 After subcutaneous administration, the median half-life of insulin human is approximately 1.5 hours (range: 40 minutes—7 hours); with higher doses (50 and 100 units), the half-life was 3.6 hours.5 The mean half-life of concentrated (U-500) insulin human in obese subjects is approximately 4.5 hours (range: 1.9—10 hours).256 When insulin human (regular) is administered IV, the mean half-life is 20 minutes after a dose of 0.1 units/kg and 1 hour after a dose of 0.2 units/kg.5 In obese subjects who received 50 and 100 unit subcutaneous doses, the mean time of termination of effect was prolonged to approximately 18 hours (range: 12—24 hours).5 In healthy subjects given isophane insulin human, the mean half-life was approximately 4.4 hours (range: 1—84 hours).6 The half-life of insulin human dry powder for inhalation ranges from 120—206 minutes; serum concentrations declined to baseline by approximately 60—240 minutes.257 Carrier particles used in insulin human dry powder for inhalation are not metabolized and are eliminated unchanged in the urine following absorption from the lungs.257 The time course of action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual and with different doses.5, 71, 75, 114, 256 Manufacturers of some insulin human products state that the effects of gender, age, obesity, renal, and hepatic impairment on the pharmacokinetics of insulin human have not been studied. 65, 71, 75, 258 The rate of absorption and onset of activity is known to be affected by the site of injection, exercise, and other variables.114, 256
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection | 100 units/mL | HumuLIN® R | Eli Lilly and Company |
NovoLIN® R | ||||
NovoLIN® R FlexPen® (available as a prefilled cartridge preassembled into pen) | Novo Nordisk | |||
500 units/mL | HumuLIN® R (concentrated U-500) | Eli Lilly and Company | ||
HumuLIN® R KwikPen® (concentrated U-500; available as a prefilled cartridge preassembled into pen) | Eli Lilly and Company |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion | 1 unit/mL in 0.9% sodium chloride | Myxredlin® | Baxter Healthcare Corporation |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral Inhalation | Powder for inhalation (contained in cartridges) | 4 units per cartridge | Afrezza® | Mannkind Corporation |
8 units per cartridge | Afrezza® | Mannkind Corporation | ||
12 units per cartridge | Afrezza® | Mannkind Corporation | ||
4 units and 8 units per cartridge | Afrezza® (titration pack) | Mannkind Corporation | ||
4 units, 8 units, and 12 units per cartridge | Afrezza® (titration pack) | Mannkind Corporation | ||
8 units and 12 units per cartridge | Afrezza® (titration pack) | Mannkind Corporation |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injectable Suspension | 100 units/mL | HumuLIN® N | Eli Lilly and Company |
HumuLIN® N KwikPen® (available as prefilled cartridge preassembled into pen) | Eli Lilly and Company | |||
NovoLIN® N | Novo Nordisk | |||
Novolin® N FlexPen® (available as prefilled cartridge preassembled into pen) | Novo Nordisk |
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injectable Suspension | Insulin Human (Regular) 30 units/mL with Isophane Insulin Human 70 units/mL | HumuLIN® 70/30 | Eli Lilly and Company |
HumuLIN® 70/30 KwikPen® (available as cartridge preassembled into pen) | Eli Lilly and Company | |||
NovoLIN® 70/30 | Novo Nordisk | |||
NovoLIN® 70/30 FlexPen® (available as cartridge preassembled into pen) | Novo Nordisk |
Only references cited for selected revisions after 1984 are available electronically.
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