HUMULIN R

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-ONLY regular, unbuffered insulin (100 units/mL) may be administered intravenously. Do NOT use Humulin R U-500 intravenously.
-The use of Novolin R in insulin pumps is not recommended because of the risk of precipitation.
-Regular insulin is available in 2 concentrations: 100 units/mL and 500 units/mL; it is essential that clinicians and patients ensure that the correct concentration of regular insulin is used. Inadvertent use of the 500 units/mL concentration in place of the 100 units/mL concentration could result in severe overdose and hypoglycemia. The 500 units/mL concentration is reserved for those patients requiring more than 200 units/day of insulin. The Humulin R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green "U-500" statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections that are unusually viscous, cloudy, discolored, or contain particulate matter or clumps. Regular insulin is clear and colorless.
-Patients using insulin vials should never share needles or syringes with another person.

Insulin Pens:
-Regular insulin is available in 2 concentrations as a prefilled pen: 100 units/mL and 500 units/mL. The 500 units/mL pen is reserved for those patients requiring more than 200 units/day of insulin.
-Insulin pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in the transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials instead, if available, or, reserve the use of any pen for 1 patient only.
-Ensure that the patient knows how to use the type of pen needles being dispensed.-For standard pen needles with both an outer cover and an inner needle cover, remove both covers before use.
-For the safety pen needle, remove only the outer cover; the fixed inner needle shield remains in place.

-Insulin should never be withdrawn from an insulin pen cartridge.
Intravenous Administration
-To accurately prepare intravenous doses, U-100 insulin syringes with a Luer connector are available and are recommended to be used to avoid dosage errors.

Direct IV Injection
-Inject desired dose of undiluted regular insulin directly into a vein or via Y-site injection or 3-way stopcock at a rate of up to 50 units/minute.


Continuous IV Infusion
-For intravenous use, Humulin R regular human insulin should be used at concentrations from 0.1 unit/mL to 1 unit/mL in infusion systems with 0.9% Sodium Chloride Injection using polyvinyl chloride infusion bags. Do NOT use Humulin R U-500 to prepare infusions.
-For intravenous use, Novolin R regular human insulin should be used at concentrations from 0.05 units/mL to 1 unit/mL in infusion systems using polypropylene infusion bags, using any of the following infusion fluids: 0.9% Sodium Chloride, 5% Dextrose, or 10% dextrose with 40 mmol/L Potassium Chloride.
-For example, an insulin infusion may be prepared by adding 100 units of regular insulin to 100 mL of 0.9% Sodium Chloride Injection to prepare an infusion concentration of 1 unit/mL.
-ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 0.2 units/mL or 1 unit/mL.
-Insulin adsorbs to plastics used for IV tubing. To minimize adsorption, fill the tubing administration set with the insulin admixture (concentration of at least 0.5 units/mL) for 20 to 30 minutes then flush with 100 mL of the insulin admixture before administration. Another source suggests that a priming volume of 20 mL of a 1 unit/mL of insulin solution is sufficient to minimize insulin adsorption to IV lines.
-Storage of insulin infusions:-Prepared with Humulin R 100 units/mL: Insulin infusions at concentrations of 0.1 to 1 unit/mL in 0.9% Sodium Chloride Injection are stable for 48 hours under refrigeration (2 to 8 degrees C or 36 to 46 degrees F) and may be used for an additional 48 hours at room temperature.
-Prepared with Novolin R 100 units/mL: Insulin infusions at concentrations of 0.05 to 1 unit/mL in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or 10% Dextrose Injection with 40 mmol/L Potassium Chloride are stable for 24 hours at room temperature.


Human Insulin Pre-mixed Infusion Solution (i.e., Myxredlin IV Solution in Galaxy Container)
-Contains 100 units/100 mL (1 unit/mL) of insulin in 0.9% Sodium Chloride injection and is a clear, colorless solution.
-For intravenous infusion only.
-Do not add supplementary medication or additives.
-Do not use in series connections.
-Storage: Refrigerate at 2 to 8 degrees C (36 to 46 degrees F) in the original carton to protect from light until administration. Do not freeze or use a solution that has been frozen. If needed, the infusion may be stored at room temperature (up to 25 degrees C or 77 degrees F) for up to 30 days in the original carton. Once stored at room temperature, do not place back in the refrigerator. Do NOT shake. Discard any unused portion.

Subcutaneous Administration
Intermittent Subcutaneous Injection
-Regular insulin is preferably administered 30 minutes before a meal.
-Double-check the insulin concentration and dosage in the syringe or injection device prior to administration. If using a pen or other injector device, prime the device prior to each injection to ensure accurate dosing.

Administration
-Subcutaneous injections are usually made into the anterior and lateral aspects of the thigh, the upper arms, buttocks, or the abdomen.
-Rotate injection sites within the same region with each injection to prevent lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring.

Regular Insulin Pens:
-Novolin R U-100 Flexpen:-The needle should remain in the skin for at least 6 seconds to ensure complete delivery of the insulin dose.
-Dials in 1 unit increments and delivers a maximum dose of 60 units per injection.
-Storage of opened Flexpen: Store in a cool place (up to 30 degrees C [86 degrees F]); do not refrigerate. Discard after 28 days. Protect from heat and light.

-Humulin R 500 units/mL KwikPen:
--The needle should remain in the skin for at least 5 seconds to ensure complete delivery of the insulin dose.
-Dials in 5 unit increments and delivers a maximum dose of 300 units per injection.
-A dose conversion is not necessary when switching between the Humulin R U-500 Kwikpen or Humulin R U-500 vial/syringe; the dose window of the U-500 pen will show the units to be injected.
-Storage of opened U-500 KwikPen: Do NOT refrigerate. Store at room temperature (up to 30 degrees C [86 degrees F]); discard after 28 days.


Regular Insulin Vials:
-Instruct patients on how to correctly draw the prescribed dose of insulin into the correct syringe. Confirm that the patient understands these directions and can correctly use the prescribed dose of insulin with the proper syringe.
-U-100 insulin syringes should be used to measure regular insulin (100 units/mL).
-U-500 insulin syringes should be used to measure concentrated regular insulin (500 units/mL). Each marking on the U-500 insulin syringe represents 5 units of insulin. Due to an increase in the risk of dosing errors, do not switch between types of syringes. Clinicians should also ensure that the prescribed dose of Humulin R U-500 is always expressed in units of insulin.
-Humulin R U-100 may be diluted with Sterile Diluent for Humulin R for subcutaneous injection ONLY under medical supervision.-Dilute 1 part Humulin R 100 units/mL to 9 parts diluent to yield a concentration one-tenth that of Humulin R (equivalent to U-10).
-Dilute 1 part Humulin R 100 units/mL to 1 part diluent to yield a concentration one-half that of Humulin R (equivalent to U-50).
-Diluted Humulin R may be used for 28 days when stored at 5 degrees C (41 degrees F) or for 14 days when stored at 30 degrees C (86 degrees F).

-Storage of opened 100 units/mL vials:-Humulin R 100 units/mL: Store in a cool place (up to 30 degrees C [86 degrees F]); discard after 31 days. Protect from heat and light.
-Novolin R 100 units/mL: Store in a cool place (up to 25 degrees C [77 degrees F]); do not refrigerate. Discard after 42 days. Protect from heat and light.

-Storage of opened Humulin R 500 units/mL vials:-Store in a refrigerator (2 to 8 degrees C [36 to 46 degrees F]) or at room temperature (up to 30 degrees C [86 degrees F]); discard after 40 days. Do not freeze. Protect from heat and light.


Mixing of Regular Insulin with Other Insulin Products
-Do NOT mix concentrated regular insulin (500 units/mL) with other insulin products or solutions.
-Be sure that the brands of insulin are compatible. For example, do not mix Humulin R with insulin preparations other than Humulin N.
-When mixing regular insulin (100 units/mL) with longer-acting insulin together in a syringe, draw regular insulin into the syringe first. This prevents contamination of the remaining regular insulin in the vial by the longer-acting insulin.
-NPH and regular insulin (100 units/mL) can be mixed together in a syringe without changes in action or potency.
-Inject immediately after mixing.

Hypoglycemia is the most common adverse reaction of insulin therapy; educate patients and caregivers about the prevention and management of hypoglycemia. Because individual patients have different thresholds, there is no single numerical definition for hypoglycemia; however, in clinical practice, a blood glucose level less than 70 mg/dL is a standard threshold for treatment in pediatric patients. Patients experiencing symptoms of hypoglycemia should be immediately given simple carbohydrate to raise blood glucose levels. Mild events can be treated with 10 to 15 grams of oral glucose; severe episodes can be treated with IV dextrose (2 to 3 mL/kg 10% Dextrose Injection) or IM/subcutaneous glucagon (0.5 to 1 mg depending on age/weight). Also, patients should ingest a full snack or meal shortly after that to prevent recurrence of hypoglycemia. Infants and young children are at greater risk for hypoglycemia; they often have unpredictable appetites and activity levels, which complicate the prediction of insulin requirements. Also, young children are often unaware of hypoglycemia symptoms, which may delay proper treatment. Physical activity also increases the risk of hypoglycemia during and immediately after exercise and again approximately 7 to 12 hours after exercise. A source of simple carbohydrate should be readily available before, during, and after exercise. Targeting aggressive blood glucose and A1C goals may also increase the risk of hypoglycemia. Less stringent A1C goals (e.g., less than 8.5%) may be appropriate for patients with a history of severe hypoglycemia or hypoglycemia unawareness. Individualize blood glucose and A1C targets with the goal of achieving the best possible control while minimizing the risk of hypoglycemia and maintaining normal growth and development. The incidence of hypoglycemia is difficult to estimate because definitions of hypoglycemia in clinical trials vary. The rate of severe hypoglycemia is thought to be 5 to 20 per 100 patient-years in children. While this rate has declined over the last decade, it is still higher than that of adults. Signs and symptoms of hypoglycemia can include hunger, pallor, nauseousness or vomiting, fatigue, sweating, head pain, palpitations, numbness of the mouth, tingling in the fingers, tremor, muscle weakness, blurred vision, confusion, tachycardia, and shallow breathing. In young children, behavioral symptoms such as irritability, sudden mood changes, crying for an unknown reason, and clumsiness may be the main presenting symptoms. In severe cases, seizures and loss of consciousness can occur and require emergency treatment. Prolonged hypoglycemia can result in irreversible brain damage and even death. Using insulin analogs rather than traditional human insulin may carry a lower risk of hypoglycemia in some patients; insulin analogs, both rapid-acting (insulin aspart, insulin glulisine, and insulin lispro) and basal insulin analogs (insulin detemir and insulin glargine), have been associated with a decreased incidence of hypoglycemia in clinical trials.

Insulin therapy has been associated with weight gain and is attributed to the anabolic effects of insulin and the decrease in glycosuria.

Insulin facilitates the intracellular uptake of potassium, therefore, hypokalemia is possible. If left untreated, hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Hypokalemia risk is increased in patients receiving insulin intravenously since it has a more rapid onset of action, in patients using potassium-lowering medications, and in patients taking medications sensitive to serum potassium concentrations. Potassium concentrations should be monitored closely when regular insulin is administered intravenously.

During insulin therapy, lipodystrophy, including both lipohypertrophy (the accumulation of subcutaneous fat around a site of injection that has been used repeatedly) and lipoatrophy (the breakdown of adipose tissue at the insulin injection site, causing a depression in the skin) may occur. During postmarketing use, cases of localized cutaneous amyloidosis at the injection site have been reported. In addition, hyperglycemia has been noted with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. An injection site reaction that is allergic in nature can also occur, resulting in pruritus, erythema, warmth/burning, and swelling at the injection site. Injection site pain, skin discoloration, hematoma, nodules/mass, and hemorrhage have also been reported with subcutaneous insulin use. These reactions usually resolve in a few days to a few weeks, but in some occasions may require discontinuation. Localized reactions and generalized myalgia have been reported with the use of metacresol, which is an excipient in the product.

Severe, life-threatening, anaphylactoid reactions, may occur with insulin products, including regular insulin. If a hypersensitivity reaction occurs, discontinue the insulin product, treat per standard of care, and monitor the patient until signs and symptoms have resolved. Local allergy to insulin may cause pruritis or urticaria, erythema, and local edema. Generalized allergy is less common, but potentially more serious and may cause whole body rash, angioedema, bronchospasm, dyspnea, wheezing, hypotension, sinus tachycardia, diaphoresis, and anaphylactic shock. Human insulin appears to be the least allergenic compared to animal-derived products, but may also cause reactions. Desensitization procedures may be necessary in some patients.

Insulin resistance occasionally can develop in patients requiring daily insulin injections. Insulin resistance can be acute resulting from infections, surgical trauma, emotional disturbances, or other endocrine disorders. Insulin resistance can also be chronic; for patients with type 2 diabetes mellitus, insulin resistance is usually associated with obesity and related to decreased tissue sensitivity to insulin. For patients with type 1 diabetes mellitus, chronic insulin resistance is often due to increased levels of circulating anti-insulin antibodies. All exogenously administered insulins have the ability to cause anti-insulin antibodies. The clinical significance of antibody formation to various insulin products is not always clear, as unpredictable changes in the pharmacokinetics and pharmacodynamics of exogenous insulin are possible in the presence of anti-insulin antibodies; however, in general, a correlation between the presence of anti-insulin antibodies with insulin dose, HbA1c, or adverse events has not been demonstrated. Corticosteroids have been used if changing to a different insulin species source is not effective.

Data concerning the effects of exogenously administered insulin on blood pressure and the development of hypertension are conflicting. Observational data indicate that an association between exogenous hyperinsulinemia and hypertension may exist, while some prospective randomized clinical trials do not report an association. In a cross-sectional study of patients with type 2 diabetes mellitus (n = 87,850) in Taiwan, the use of exogenous insulin (n = 5,927) was associated with increased odds of hypertension (defined a systolic blood pressure of 140 mmHg or more or diastolic blood pressure 90 mmHg or more). Compared to patients not using insulin, the odds of hypertension for patients using insulin for less than 5 years, 5 to 9 years, or 10 years or more was 1.14 (95% CI 1.06 to 1.23), 1.35 (95% CI 1.18 to 1.54), and 1.46 (95% CI 1.24 to 1.74), respectively. The odds of hypertension were substantially higher in those patients that did not have a diagnosis of hypertension when starting insulin therapy. Compared to patients not using insulin, the odds of a new diagnosis of hypertension after using insulin for 5 to 9 years or for 10 years or more was 1.5 (95% CI 1.25 to 1.80) and 2.15 (95% CI 1.72 to 2.70). While the data are conflicting and not definitive, clinicians should be aware of the possibility that exogenous insulin may increase blood pressure in type 2 diabetes patients and manage their patients with antihypertensive agents as indicated.

Peripheral edema may occur in patients taking insulin therapy. Sodium retention and edema are especially possible if previously poor metabolic control is improved by intensified insulin therapy.

Headache has been reported infrequently in clinical trials of various insulin products. In some cases, headache may be a symptom of low blood sugar.

Regular insulin is contraindicated for use in patients hypersensitive to the insulin or the excipients in the formulations. Regular insulin contains m-cresol and should be used cautiously in patients with m-cresol hypersensitivity; localized reactions and general myalgias have been reported with the use of cresol as an injectable excipient. If a hypersensitivity reaction occurs, discontinue the insulin product, treat per standard of care, and monitor the patient until signs and symptoms have resolved. Minor, local sensitivity characterized by redness, swelling, or itching at the site of injection does not usually contraindicate therapy. Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash, pruritus, angioedema, bronchospasm, wheezing, hypotension, tachycardia, and diaphoresis. Severe cases, including anaphylactoid reactions and shock, may be life threatening.

Fever, thyroid disease, infection, recent trauma or surgery, diarrhea secondary to malabsorption, vomiting, and certain medications can affect insulin requirements, requiring dosage adjustments. Diabetic patients should be given a 'sick-day' plan to take appropriate action with blood glucose monitoring and insulin therapy when acute illness is present.

Hepatic disease, renal impairment, or renal failure may affect insulin dosage requirements; frequent blood glucose monitoring and insulin dosage reduction may be required. Some pharmacokinetic studies have shown increased circulating levels of insulin in patients with hepatic or renal failure. Individualize dosage based on blood glucose and other clinical parameters.

Do not give concentrated regular insulin (500 units/mL) via intravenous administration, intramuscular administration, or via an insulin pump. In addition, the 500 unit/mL concentration should not be diluted or mixed with any other insulin products or solutions. Regular insulin (100 units/mL) is also not for intramuscular use, but can be administered via intravenous administration; the American Diabetes Association recommends that regular insulin by continuous intravenous infusion be used to treat hyperglycemic crisis including diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) (and diabetic coma) unless it is considered mild.

Insulin is contraindicated in patients during episodes of hypoglycemia. Hypoglycemia is the most common adverse effect of insulin therapy and a major barrier to achieving optimal glycemic control long term. Educate patients and caregivers on the signs and symptoms of hypoglycemia, risk factors, and management strategies. Hypoglycemia can happen suddenly and symptoms may differ in individuals and change over time in the same individual. Neonates, infants, and young children are at particular risk for hypoglycemia; they often have unpredictable appetites and activity levels, which complicate prediction of insulin requirements. In addition, young children are often unaware of hypoglycemia symptoms, which may delay proper treatment. Individualize blood glucose and A1C targets with the goal of achieving the best possible control while minimizing the risk of hypoglycemia and maintaining normal growth and development. Physical activity increases the risk of hypoglycemia during and immediately after exercise and again approximately 7 to 12 hours after exercise. A source of simple carbohydrate should be readily available before, during, and after exercise. Targeting aggressive blood glucose and A1C goals may also increase the risk of hypoglycemia. Although the A1C target is less than 7.5% across pediatric age groups in general, less stringent goals (e.g., less than 8.5%) may be appropriate for patients with a history of severe hypoglycemia and hypoglycemia unawareness. Symptomatic awareness may be blunted or masked in patients using medications that block the sympathetic nervous system (e.g., beta-blockers), those who experience recurrent hypoglycemia, or in those with longstanding diabetes or diabetic nerve disease. Patients with renal or hepatic impairment may be at higher risk for hypoglycemia. Changes in insulin, manufacturer, type, or method or site of administration may also affect glycemic control. 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. Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. It is essential that clinicians and patients ensure the correct insulin is dispensed and administered; this includes the correct insulin brand and concentration. The Humulin R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green "U-500" statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes. Dosing errors have occurred when Humulin R U-500 was administered with syringes other than a U-500 insulin syringe. Only a U-500 insulin syringe should be used with Humulin R U-500 in order to avoid administration errors. Clinicians must also determine that patients and/or caregivers can draw up the correct insulin dosage before prescribing and dispensing. Insulin from a pen should NOT be transferred into a syringe for administration as overdose and severe hypoglycemia can occur.

In addition to hypoglycemia, hypokalemia may also occur because insulin facilitates the intracellular uptake of potassium. Untreated hypokalemia may result in respiratory paralysis, ventricular arrhythmia, and even death. Patients at risk for hypokalemia (e.g., patients using potassium-lowering drugs, taking potassium concentration sensitive drugs, or receiving insulin via continuous IV infusion) should be monitored closely for these effects, and potassium should be replaced as clinically indicated.

Monitor blood glucose for needed insulin dosage adjustments in insulin-dependent diabetic patients whenever a change in either nicotine intake or tobacco smoking status occurs. Nicotine activates neuroendocrine pathways (e.g., increases in circulating cortisol and catecholamine levels) and may increase plasma glucose. Tobacco smoking is known to aggravate insulin resistance. The cessation of nicotine therapy or tobacco smoking may result in a decrease in blood glucose or an increase the subcutaneous absorption of insulin, respectively.

Use caution when prescribing regular insulin to patients with compromised vision due to a potential for dosing errors. Patients with visual impairment may rely on audible clicks from insulin pens to dial their dose; preparing the injection by using audible clicks may result in dosing errors.

Description: Regular insulin is a short-acting insulin. Regular insulin is used in both type 1 and type 2 diabetes mellitus (DM) in pediatric patients. In pediatric patients with type 2 DM, insulin is used when oral hypoglycemic agents fail to provide adequate glycemic control or are not tolerated. Regular insulin and the rapid-acting insulin analogs (insulin aspart, insulin glulisine, and insulin lispro) are often given as prandial or snack boluses due to their pharmacokinetic profiles. Regular insulin and the rapid-acting analogs are considered equipotent. However, all of the rapid-acting analogs have a quicker onset of action when compared to regular insulin, reach maximal concentrations faster, have less absorption variation, and have a shorter duration of action. Regular insulin may be administered intravenously to treat diabetic ketoacidosis (DKA), other hyperglycemic crises, or emergent hyperkalemia. Regular insulin has been studied in very low birth weight neonates to promote growth, however, the benefits of routine use do not outweigh the risks. Insulin adsorbs to plastics used for IV tubing. Preflushing the tubing prior to intravenous administration allows for more predictable insulin delivery and response. In a study comparing flushed and nonflushed IV insulin administration in preterm neonates, there was a 2-hour lag time in the nonflushed system, which could lead to hypoglycemia in patients when increasing the insulin infusion. Regular insulin is FDA-approved in pediatric patients; no minimum age is specified, and regular insulin is used in patients as young as neonates.

General Dosing Information
-Regular insulin is available in 2 concentrations: 100 units/mL and 500 units/mL. It is essential that clinicians and patients ensure that the correct concentration of regular insulin is used. Inadvertent use of the 500 units/mL concentration in place of the 100 units/mL concentration could result in severe overdose and hypoglycemia. The 500 units/mL concentration is reserved for those patients requiring more than 200 units of insulin daily.
-The Humulin R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green "U-500" statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes.
-Dosing errors have occurred when Humulin R U-500 was administered with syringes other than a U-500 insulin syringe. ONLY a U-500 insulin syringe should be used with Humulin R U-500 to avoid administration errors.

For the treatment of type 2 diabetes mellitus:
Subcutaneous dosage:
Children and Adolescents: Specific dosing recommendations are not available. 0.25 to 0.5 units/kg/day of intermediate-acting or basal insulin is generally effective in achieving glycemic control and facilitating transition to metformin monotherapy. If target HbA1c is not achieved within 4 months of metformin monotherapy, consider readding basal insulin; add prandial insulin if target HbA1c is not achieved on combination metformin and basal insulin (up to 1.5 units/kg).

For the treatment of neonatal diabetes mellitus*:
Continuous Intravenous Dosage:
Neonates and Infants: A continuous IV infusion may be used to initially control blood glucose concentrations and determine insulin requirements in newly diagnosed neonates and infants. Although specific recommendations for initiating the insulin infusion are not available, continuous infusion of insulin at a dose of 0.01 to 0.1 units/kg/hour IV have been used in neonates and infants for other indications. Of note, neonates can be very sensitive to the effects of insulin; titrate the dose carefully to desired blood glucose concentrations with frequent monitoring. After stabilization and requirements have been determined, patients are typically converted to multiple daily subcutaneous injections of regular insulin or rapid acting insulin with a long acting insulin analog or continuous subcutaneous insulin infusion via an insulin pump with a rapid acting insulin analog.
Subcutaneous Dosage:
Continuous subcutaneous insulin infusion (CSII) may be preferred by some clinicians as it offers several advantages over multiple daily injections. CSII is more representative of physiologic insulin, is easier to manage, and has been shown to improve long-term metabolic control with reduced hypoglycemia episodes.
Neonates and Infants: Typical insulin dosage requirements range from 0.29 to 1.4 units/kg/day subcutaneously. Regular insulin (mealtime insulin) in combination with a basal insulin can be used, although a rapid acting analog may be preferred when using multiple daily injections. In breast or bottle fed neonates, the mealtime insulin accounts for about 70% of the daily insulin requirement. In infants, mealtime insulin accounts for 50% to 70% of the daily insulin requirement. The mealtime insulin doses should be divided equally and administered prior to each feeding/meal. Monitor blood glucose concentrations prior to each meal and adjust insulin doses as necessary.

For the treatment of diabetic ketoacidosis:
Intravenous dosage:
Infants, Children, and Adolescents: 0.05 to 0.1 unit/kg/hour continuous IV infusion beginning at least 1 hour after starting fluid replacement therapy and continuing until the acidosis is corrected. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated. When transferring from intravenous to subcutaneous insulin, administer the first subcutaneous injection of rapid-acting insulin 15 to 30 minutes before discontinuing the insulin infusion to ensure sufficient time for insulin absorption and prevent rebound hyperglycemia during the transition period; for basal insulin, allow a longer overlap and gradually decrease the intravenous insulin infusion rate.
Subcutaneous dosage:
Infants, Children, and Adolescents: 0.13 to 0.17 units/kg/dose subcutaneously every 4 hours, initially. Adjust dose by 10% to 20% based on blood glucose concentration before the next insulin injection; may increase frequency to every 2 or 3 hours if acidosis is not improving. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated. Subcutaneous administration of short-acting (regular) insulin is an alternative in mild diabetic ketoacidosis when intravenous insulin infusion or rapid-acting insulin analogs are not available.

For the treatment of hyperosmolar hyperglycemic state (HHS):
Continuous Intravenous Infusion dosage:
Children and Adolescents : 0.025 to 0.05 units/kg/hour continuous IV infusion once serum glucose concentrations are no longer declining at a rate of at least 50 mg/dL/hour with fluid administration. Monitor blood glucose concentrations hourly and adjust the insulin infusion rate to achieve a decrease in glucose concentration of 50 to 75 mg/dL/hour. Suspend insulin therapy if the serum glucose concentration decreases by more than 100 mg/dL/hour. Fluid administration alone will substantially decrease serum glucose concentrations. Early insulin administration is unnecessary in non-ketotic HHS and may increase the risk of death. Only initiate insulin if needed; insulin should be used earlier in patients with more severe ketosis and acidosis.

For nutritional supplementation* to maintain normoglycemia in very low birthweight neonates with persistent glucose intolerance, including those neonates on parenteral nutrition with persistent glucose intolerance:
Continuous Intravenous Infusion dosage:
Premature Neonates: 0.05 units/kg/hour IV continuous infusion adjusted to maintain blood glucose concentrations within normal ranges (e.g., 72 to 108 mg/dL in one study and 72 to 144 mg/dL in another). Neonates are especially sensitive to insulin, and an insulin regimen may rapidly induce hypoglycemia and hypokalemia. Monitor blood glucose and other parameters extremely closely. Blood glucose and potassium concentrations should be obtained every 1 to 2 hours. Based on a systematic review, the routine administration of continuous insulin infusion for promoting growth is not recommended. The benefits do not outweigh the risk of potential hypoglycemia, injuries related to routine heel sticks for blood sampling, and the cost of infusion and blood glucose monitoring.

For the treatment of hyperkalemia*:
Continuous Intravenous Infusion dosage:
Neonates: 0.05 to 0.2 units/kg/hour continuous infusion; given with continuous dextrose infusion. A prolonged and gradual tapering of insulin and glucose is recommended because rapid cessation can cause hypoglycemia. In a study of 12 premature neonates born at 28 weeks gestation or less with a serum potassium concentration of more than 7 mEq/L, 0.05 to 0.1 units/kg/hour of insulin was given with existing intravenous fluids to 7 patients and 5 received rectal sodium polystyrene sulfonate. There was a significant decrease in serum potassium concentrations compared with the sodium polystyrene sulfonate-treatment group in the first 6 hours of therapy (p = 0.002). Premature neonates tolerated doses up to 0.2 units/kg/hour for 12 to 36 hours. In a study of 12 premature neonates (24 to 26 weeks gestational age) with hyperkalemia, an average insulin dose of 0.2 units/kg/hour was administered with 0.5 grams glucose/kg/hour. All premature neonates showed initial control in hyperkalemia. Hyperglycemia was a problem during this study and a decrease in glucose delivery or increase in insulin dose resolved hyperglycemia in most of the neonates. Dextrose/insulin infusion was decreased when hyperkalemia started resolving, after a mean duration of approximately 6 hours. The average duration of treatment was 29 hours.
Infants, Children, and Adolescents: Dextrose 0.5 to 1 gram/kg/hour (using 20% Dextrose Injection) combined with insulin 0.2 units IV for every gram of glucose administered.

For the treatment of beta-blocker toxicity* or calcium-channel blocker toxicity*:
Continuous Intravenous Infusion dosage:
Infants, Children, and Adolescents: 1 unit/kg IV followed by 0.5 to 1 unit/kg/hour continuous IV infusion. In the presence of myocardial dysfunction, titrate incrementally up to 10 units/kg/hour to achieve desired contractility or blood pressure. Monitor glucose and potassium concentrations; maintain euglycemia with a dextrose infusion.

For the treatment of type 1 diabetes mellitus:
Subcutaneous dosage:
Infants, Children, and Adolescents: 55% to 70% of the total daily insulin dose subcutaneously divided 2 to 3 times daily approximately 30 minutes before meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.

Therapeutic Drug Monitoring:
-Individualize glycemic goals based on the risk-benefit assessment.
-Monitor post-prandial glucose concentrations if there is an inconsistency between pre-prandial glucose and A1C concentrations and to help assess basal-bolus regimens.

Blood glucose goals for children and adolescents with type 1 diabetes :-Pre-prandial = 70 to 130 mg/dL
-Post-prandial = 90 to 180 mg/dL
-Bedtime/overnight = 80 to 140 mg/dL
-Prior to exercise = 126 to 180 mg/dL

A1C goals for children and adolescents with type 1 diabetes :-Assess A1C every 3 months in most patients or more frequently as clinically indicated.
-In general, the A1C target is less than 7% across all pediatric age groups. A lower goal of less than 6.5% is reasonable if it can be achieved without excessive hypoglycemia, negative impacts on well-being, undue burden of care, or in those who have nonglycemic factors that decrease A1C (e.g., lower erythrocyte life span) or during the honeymoon phase. A less stringent A1C goal of less than 7.5% may be appropriate for patients with a history of hypoglycemia unawareness; patients who can't articulate hypoglycemia symptoms; lack access to analog insulins, advanced insulin delivery technology, and/or continuous glucose monitors; cannot check blood glucose regularly; or have nonglycemic factors that increase A1C (e.g., high glycators). A goal of less than 8% is appropriate for patients with a history of severe hypoglycemia, limited life expectancy, or where the harms of treatment are greater than the benefits.

A1C goals for children and adolescents with type 2 diabetes :
-Assess A1C every 3 months in most patients or more frequently as clinically indicated.
-In general, the A1C target is less than 7%. A lower goal of less than 6.5% is reasonable if it can be achieved without excessive hypoglycemia or adverse effects of treatment. Appropriate patients may include those with a short duration of diabetes and lesser degrees of beta-cell dysfunction and individuals treated with lifestyle or metformin only who achieve significant weight improvement. A less stringent A1C goal of less than 7.5% may be appropriate for patients with an increased risk of hypoglycemia.

Maximum Dosage Limits:
Specific maximum dosage information is not available. Individualize dosage based on careful monitoring of blood glucose and other clinical parameters in all patient populations.

Patients with Hepatic Impairment Dosing
Frequent blood glucose monitoring and insulin dosage reduction may be required in patients with hepatic impairment. Individualize dosage based on blood glucose and other clinical parameters.

Patients with Renal Impairment Dosing
Frequent blood glucose monitoring and insulin dosage reduction may be required in patients with renal impairment. Individualize dosage based on blood glucose and other clinical parameters.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Endogenous insulin regulates carbohydrate, fat, and protein metabolism by several mechanisms; in general, insulin promotes the storage and inhibits the breakdown of glucose, fat, and amino acids. Insulin lowers glucose concentrations by facilitating the uptake of glucose in muscle and adipose tissue and by inhibiting hepatic glucose production (glycogenolysis and gluconeogenesis). Insulin also regulates fat metabolism by enhancing the storage of fat (lipogenesis) and inhibiting the mobilization of fat for energy in adipose tissues (lipolysis and free fatty acid oxidation). Finally, insulin is involved in the regulation of protein metabolism by increasing protein synthesis and inhibiting proteolysis in muscle tissue.

Diabetes mellitus type 1 is caused by insulin deficiency while diabetes mellitus type 2 is caused by a combination of insulin deficiency and resistance. Biosynthetic insulin is used to regulate glucose metabolism in patients with diabetes mellitus. Insulin administration also enables these patients to replete their liver glycogen stores and to convert glycogen to fat. Commercially available insulin is prepared using recombinant DNA technology (utilizing S. cerevisiae yeast [baker's yeast]) to create a product identical in structure and function to endogenous human insulin.

Pharmacokinetics: Regular insulin is administered via the intravenous or subcutaneous routes. Endogenous insulin distributes widely throughout the body. Uptake and degradation occurs predominantly in the liver, kidney, muscle, and adipocytes. The liver is the primary organ involved in insulin clearance.

Affected cytochrome P450 (CYP450) isoenzymes or drug transporters: None


-Route-Specific Pharmacokinetics
Intravenous Route
The onset of action is within 10 to 15 minutes with a duration of action of 2 to 6 hours (median: 4 hours). For the premixed insulin infusion (Myxredlin), the average onset of action was approximately 21 minutes after the start of the IV infusion administration. The glucose infusion rate gradually increased to a maximum response of 13.7 mg/kg/minute after 5 hours of human insulin infusion. The mean terminal half-life after stopping the IV infusion was estimated to be 23.4 minutes.

Subcutaneous Route
Subcutaneously administered regular insulin is best given 30 minutes before a meal. The onset of action of unbuffered, regular insulin (100 units/mL) begins approximately 30 minutes (range: 10 to 75 minutes) after injection with maximal effects occurring 1.5 and 3.5 hours post-dose. The apparent plasma half-life after subcutaneous administration is approximately 1.5 hours with a duration of action of 8 hours (mean 5 to 7 hours, actual values can widely among individuals receiving subcutaneous regular insulin). The onset of action of unbuffered, regular insulin (500 units/mL) is similar to the onset of unbuffered, regular insulin (100 units/mL); however, due to its concentrated nature, the duration of action of unbuffered, regular insulin (500 units/mL) is considerably longer (mean 21 hours, range: 13 to 24 hours). Median Cmax of regular insulin (500 units/mL) occurs between 4 to 8 hours (range: 0.5 to 8 hours). Buffered regular insulin is for subcutaneous use only, and should not be mixed with other insulin types due to the phosphate buffer. The pharmacokinetics of buffered regular insulin are identical to those of unbuffered, regular insulin (100 units/mL) administered by the subcutaneous route.