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Insulin Regular

Medically reviewed on Nov 15, 2018

Pronunciation

See also: Basaglar

(IN soo lin REG yoo ler)

Index Terms

  • Regular Insulin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

HumuLIN R: 100 units/mL (3 mL, 10 mL) [contains metacresol]

NovoLIN R: 100 units/mL (10 mL) [contains metacresol]

NovoLIN R ReliOn: 100 units/mL (10 mL) [contains metacresol]

Solution, Subcutaneous:

HumuLIN R U-500 (CONCENTRATED): 500 units/mL (20 mL) [contains metacresol]

Solution Pen-injector, Subcutaneous:

HumuLIN R U-500 KwikPen: 500 units/mL (3 mL) [contains metacresol]

Brand Names: U.S.

  • HumuLIN R U-500 (CONCENTRATED)
  • HumuLIN R U-500 KwikPen
  • HumuLIN R [OTC]
  • NovoLIN R ReliOn [OTC]
  • NovoLIN R [OTC]

Pharmacologic Category

  • Insulin, Short-Acting

Pharmacology

Insulin acts via specific membrane-bound receptors on target tissues to regulate metabolism of carbohydrate, protein, and fats. Target organs for insulin include the liver, skeletal muscle, and adipose tissue.

Within the liver, insulin stimulates hepatic glycogen synthesis. Insulin promotes hepatic synthesis of fatty acids, which are released into the circulation as lipoproteins. Skeletal muscle effects of insulin include increased protein synthesis and increased glycogen synthesis. Within adipose tissue, insulin stimulates the processing of circulating lipoproteins to provide free fatty acids, facilitating triglyceride synthesis and storage by adipocytes; also directly inhibits the hydrolysis of triglycerides. In addition, insulin stimulates the cellular uptake of amino acids and increases cellular permeability to several ions, including potassium, magnesium, and phosphate. By activating sodium-potassium ATPases, insulin promotes the intracellular movement of potassium.

Normally secreted by the pancreas, insulin products are manufactured for pharmacologic use through recombinant DNA technology using either E. coli or Saccharomyces cerevisiae. Regular insulin has an identical structure to that of native human insulin. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin regular is a short-acting insulin analog.

Distribution

IV, SubQ: Vd: 0.26 to 0.36 L/kg

Excretion

Urine

Onset of Action

SubQ: 0.25 to 0.5 hours; Peak effect: SubQ: U-100: 2.5 to 5 hours; U-500: 4 to 8 hours

Time to Peak

Plasma: SubQ: 0.8 to 2 hours

Duration of Action

IV: U-100: 2 to 6 hours

SubQ: U-100: 4 to 12 hours (may increase with dose); U-500: 13 to 24 hours

Half-Life Elimination

IV: ~0.5 to 1 hour (dose-dependent); SubQ: 1.5 hours

Use: Labeled Indications

Diabetes mellitus, types 1 and 2: Treatment of type 1 diabetes mellitus and type 2 diabetes mellitus to improve glycemic control.

Note: Concentrated U-500 regular insulin is indicated only in patients requiring more than 200 units of insulin per day.

Off Label Uses

Cadaveric organ recovery (hormonal resuscitation)

Data from three retrospective cohort studies of brain-dead donors who successfully donated organs suggests that the use of intravenous regular insulin (and dextrose) given concomitantly with levothyroxine or liothyronine, methylprednisolone, and vasopressin may be beneficial for hemodynamically unstable brain-dead donors to increase the quantity and quality of organs available for transplantation [Rosendale 2003a], [Rosendale 2003b], [Salim 2007]. Additional data may be necessary to further define the role of regular insulin in this setting.

Based on a consensus document sponsored by the American Society of Transplant Surgeons and the American Society of Transplantation, the use of regular insulin (in combination with vasopressin, methylprednisolone, and liothyronine) is effective and recommended for hormonal resuscitation in brain-dead donors [Rosengard 2002], [Zaroff 2002].

Diabetic ketoacidosis

Based on the American Diabetes Association consensus statement on hyperglycemic crises in adult patients with diabetes, insulin regular is effective and recommended for the treatment of patients with diabetic ketoacidosis [Kitabchi 2009].

Gestational diabetes mellitus

Based on the American Diabetic Association (ADA) guidelines for the Standards of Medical Care in Diabetes, insulin is effective and recommended in the treatment of gestational diabetes mellitus (preferred therapy) [ADA 2018].

Hyperglycemia during critical illness

Data from two prospective, randomized, controlled trials in the ICU population supports the use of insulin regular in the management of hyperglycemia in this patient population [Van den Berghe G 2001], [Van den Berghe G 2006]. However, some data suggests that intensive glucose control is not associated with reduced mortality or morbidity in the general critically ill adult patient or may even increase mortality [NICE-SUGAR Study Investigators 2009], [Wiener 2008]. The 2011 ACP clinical practice guideline for the management of glycemic control in hospitalized patients recommends against the use of intensive insulin therapy in non-SICU/MICU patients which includes patients suffering a myocardial infarction. Therefore, the 2012 SCCM guidelines suggests a glycemic goal range of 100 to 150 mg/dL.

Based on the Society of Critical Care Medicine (SCCM) guidelines for the use of an insulin infusion for the management of hyperglycemia in critically ill patients, insulin regular is an effective and recommended treatment option in this patient population to reduce the risk of morbidity and mortality in specific ICU subpopulations (eg, perioperative, postoperative cardiac surgery, post-traumatic injury, and neurologic injury patients) and the general ICU patient, respectively.

Hyperkalemia

Based on the American Heart Association (AHA) guidelines for cardiopulmonary resuscitation and emergency cardiovascular care, insulin regular (in combination with glucose) is effective and recommended in the management of severe cardiotoxicity or cardiac arrest due to hyperkalemia [AHA [Vanden Hoek 2010]].

Hyperosmolar hyperglycemic state

Based on the American Diabetes Association consensus statement on hyperglycemic crises in adult patients with diabetes, insulin regular is effective and recommended for the treatment of patients with hyperosmolar hyperglycemic state [Kitabchi 2009].

Contraindications

Hypersensitivity to regular insulin or any component of the formulation; during episodes of hypoglycemia.

Documentation of allergenic cross-reactivity for insulin is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Note: Regular insulin is a short-acting insulin. Insulin requirements vary dramatically between patients, and therapy requires dosage adjustments with careful medical supervision.

Diabetes mellitus, type 1: SubQ:

Note: Regular insulin must be used concomitantly with intermediate- or long-acting insulin (ie, multiple daily injection regimen) or in a continuous subcutaneous infusion pump. The total daily doses (TDD) presented below are expressed as the total units/kg/day of all insulin formulations combined.

General insulin dosing (off-label):

Initial TDD: ~0.4 to 0.5 units/kg/day (AACE/ACE [Handelsman 2015]; ADA 2018); conservative initial doses of 0.2 to 0.4 units/kg/day may be considered to avoid the potential for hypoglycemia; higher initial doses may be required in patients who are obese, sedentary, or presenting with ketoacidosis (AACE/ACE [Handelsman 2015]; ADA 2018).

Usual TDD maintenance range: 0.4 to 1 units/kg/day in divided doses (ADA 2018)

Division of TDD (multiple daily injections):

Basal insulin: Generally, 40% to 50% of the TDD is given as basal insulin (intermediate [NPH]- or long-acting [eg, glargine, degludec, detemir]) in 1 to 2 daily injections (AACE/ACE [Handelsman 2015]; ADA 2018).

Prandial insulin: The remaining portion (ie, 50% to 60%) of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, lispro, aspart, glulisine, insulin for inhalation) or short-acting (regular) insulin (AACE/ACE [Handelsman 2015]; ADA 2018).

Dose adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Adjust dose to maintain premeal and bedtime glucose in target range. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen that most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component.

Diabetes mellitus, type 2 (off-label): SubQ: Note: Rapid-acting analogs may be preferred over regular insulin for prandial insulin coverage due to their more rapid onset of action; however, regular insulin may be a practical option for some patients (ADA 2018; Lipska 2017).

Initial: 4 to 6 units or0.1 unit/kg or 10% of the basal insulin dose (ADA 2018; Lipska 2017) administered before the largest meal of the day and usually given in addition to a regimen that includes basal insulin (ie, a long-acting insulin such as glargine, degludec, or detemir; or an intermediate-acting insulin such as NPH) and metformin +/- other noninsulin agents (ADA 2018). Consider reducing the basal insulin dose if HbA1c is <8% when initiating prandial insulin.

Dosage adjustment:

To reach self-monitoring glucose target: Adjust prandial insulin dose by 10% to 15% or 1 to 2 units; may adjust at weekly or twice weekly intervals (ADA 2018).

For hypoglycemia: If no clear reason for hypoglycemia, decrease prandial insulin dose by 2 to 4 units or by 10% to 20% (ADA 2018).

HbA1cstill not controlled despite titrations to reach glycemic targets: One option is to advance to 'basal-bolus' (ie, prandial insulin coverage before ≥2 meals per day) in addition to basal insulin and usually given in addition to metformin +/- other noninsulin agents (ADA 2018).

Conversion from U100 insulins (primarily basal-bolus analog regimen) to concentrated U-500 regular insulin (off-label dosing) (Bergen 2017; Hood 2015): Patients requiring >200 units of insulin/day:

Initial: Discontinue all other insulins; U-500 may be initiated conservatively with 80% of the TDD of the previous regimen (rounding down to the nearest 5 units); may administer in 2 divided doses (60% prior to morning meal; 40% prior to evening meal) or in 3 divided doses (40% prior to morning meal and 30% prior to lunch and evening meals). Alternatively, if hemoglobin A1c >8% or average blood glucose ≥183 mg/dL in the 7 days prior, may consider initiating U-500 with 100% of previous TDD administered in 2 or 3 divided doses.

Titration: Note: Base dosage adjustments on the median pre-meal glucose readings obtained over previous 3 days. With 3 times daily dosing, titrate at most 2 of the 3 doses, prioritizing for hypoglycemia; round to nearest 5 units.

Blood glucose <80 mg/dL: Reduce dose by 10%

Blood glucose 80 to 130 mg/dL: No change in dose

Blood glucose 131 to 180 mg/dL: Increase dose by 5%

Blood glucose 181 to 230 mg/dL: Increase dose by 10%

Blood glucose >230 mg/dL: Increase dose by 15%

Missed meal: Decrease U-500 dose by 50% for that meal

Patients with diabetes receiving enteral feedings (off-label; ADA 2018): SubQ: Note: TDD of insulin is divided into a basal component (intermediate- or long-acting insulin) and nutritional and correctional components (regular insulin or rapid-acting insulins).

Nutritional/Correctional: SubQ: 1 unit of regular insulin per 10 to 15 g of carbohydrate plus correctional regular insulin (as needed for hyperglycemia) administered every 6 hours or prior to each bolus feeding.

Patients with diabetes receiving parenteral feedings (off-label; ADA 2018):

IV (added to TPN solution): 1 unit of regular insulin per 10 g of carbohydrate added to TPN IV solution; adjust dose daily. One option is to increase the amount of regular insulin added to the TPN by two-thirds of the amount of the correctional insulin used on the previous day (ASPEN [Mueller 2012]).

SubQ: Administer correctional regular insulin every 6 hours as needed for hyperglycemia.

Patients with diabetes undergoing surgery and using CSII pump (off-label; ADA 2018): On the morning of surgery or procedure, give 60% to 80% of the usual dose of pump “basal” insulin (rapid-or short-acting insulins) dose.

Cadaveric organ recovery (hormonal resuscitation) (off-label use): IV: Continuous infusion of 1 unit/hour (minimum dose) to maintain blood glucose of 120 to 180 mg/dL or 20 units as a bolus dose (after an IV bolus of dextrose 25 g) administered to the brain-dead donor who is hemodynamically unstable requiring significant vasopressor support; give concomitantly with levothyroxine or liothyronine (preferred), vasopressin, and methylprednisolone (Rosendale 2003a; Rosendale 2003b; Rosengard 2002; Salim 2007; Zaroff 2002).

Diabetic ketoacidosis (off-label use) (Kitabchi 2009): Only IV regular insulin should be used for severe diabetic ketoacidosis (pH <7, serum bicarbonate <10, and/or stupor/coma) or in patients with hypotension, anasarca, or critical illness. Treatment should continue until resolution of ketoacidosis (blood glucose <200 mg/dL and two of the following: Serum bicarbonate ≥15, venous pH >7.3, anion gap ≤12). Serum glucose is not a direct indicator of these abnormalities and may decrease more rapidly than correction of the ketoacidosis. Also, refer to institution-specific protocols where appropriate.

IV:

Bolus: 0.1 units/kg (optional)

Infusion: If a bolus was administered, follow with 0.1 units/kg/hour. If no bolus was administered, initiate with 0.14 units/kg/hour (lower doses may not achieve adequate insulin concentrations to suppress hepatic ketone body production).

Adjustment: If serum glucose does not fall by at least 10% in the first hour, give an IV bolus of 0.14 units/kg and continue previous regimen. In addition, if serum glucose does not fall by 50 to 75 mg/dL in the first hour, the insulin infusion dose should be increased hourly until a steady glucose decline is achieved Once serum glucose reaches 200 mg/dL, decrease infusion dose to 0.02 to 0.05 units/kg/hour or switch to SubQ rapid-acting insulin (eg, aspart, lispro) at 0.1 units/kg every 2 hours; administer dextrose-containing IV fluids to maintain serum glucose between 150 to 200 mg/dL until the resolution of ketoacidosis.

Transition from IV to SubQ insulin: After resolution of diabetic ketoacidosis, supplement IV insulin with SubQ insulin as needed until the patient is able to eat and transition fully to a SubQ insulin regimen. An overlap of ~1 to 2 hours between discontinuation of IV insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels; for basal insulin analogues (eg, degludec, detemir, glargine), may consider an overlap of 3 to 4 hours due to their delayed onset of action (Fayfman 2017).

SubQ, IM: Frequent administration of SubQ or IM insulin regular has shown efficacy in diabetic ketoacidosis treatment; however, continuous IV insulin therapy is preferred (especially with severe ketoacidosis) due to a shorter half-life and ease of titration. SubQ administration may be considered in the non-ICU setting for mild to moderate ketoacidosis, but rapid-acting insulins (lispro and aspart) are preferred (Kitabchi 2009).

Hyperglycemia, critically ill (off-label use): Adults: IV continuous infusion: Insulin therapy should be implemented when blood glucose ≥150 mg/dL with a goal to maintain blood glucose <150 mg/dL (with values absolutely <180 mg/dL) using a protocol that achieves a low rate of hypoglycemia (ie, ≤70 mg/dL). Alternatively, other rapid acting insulin analogues (eg, insulin aspart or insulin glulisine) may also be used as a continuous infusion to maintain glycemic control (in place of regular insulin). Before discontinuation, stable ICU patients should be transitioned to a protocol-driven basal/bolus insulin regimen, based on insulin infusion history and carbohydrate intake, to avoid loss of glycemic control. Subcutaneous insulin therapy may be considered for selected clinically stable ICU patients (SCCM [Jacobi 2012]). Note: The Surviving Sepsis Campaign guidelines recommend initiating insulin dosing in patients with severe sepsis when 2 consecutive blood glucose concentrations are >180 mg/dL and to target an upper blood glucose ≤180 mg/dL (Rhodes 2017).

Hyperkalemia, moderate to severe (off-label use): IV: 10 units regular insulin mixed with 25 g dextrose (50 mL D50W) given over 15 to 30 minutes (AHA [Vanden Hoek 2010]) or alternatively, 10 units regular insulin as IV bolus followed by 50 mL D50W administered over 5 minutes (Allon 1990); a weight-based insulin dose of 0.1 units/kg (maximum: 10 units) may also be considered to reduce the risk of hypoglycemia (Brown 2018; Wheeler 2016). Effects on potassium are temporary; repeat dosing as needed (AHA [Vanden Hoek 2010]). As appropriate, consider methods of enhancing potassium removal/excretion.

Hyperosmolar hyperglycemic state (off-label use) (Kitabchi 2009): Only regular injectable insulin should be used. Infusion should continue until reversal of mental status changes and hyperosmolality. Serum glucose is not a direct indicator of these abnormalities, and may decrease more rapidly than correction of the metabolic abnormalities. Also, refer to institution-specific protocols where appropriate.

IV:

Bolus: 0.1 units/kg bolus (optional)

Infusion: If a bolus was administered, follow with 0.1 units/kg/hour. If no bolus was administered, initiate with 0.14 units/kg/hour.

Adjustment: If serum glucose does not fall by at least 10% in the first hour, give an IV bolus of 0.14 units/kg and continue previous regimen. In addition, if serum glucose does not fall by 50 to 75 mg/dL in the first hour, the insulin infusion dose should be increased hourly until a steady glucose decline is achieved. Once serum glucose reaches 300 mg/dL, decrease dose to 0.02 to 0.05 units/kg/hour; administer dextrose-containing IV fluids to maintain serum glucose between 200 to 300 mg/dL until the patient is mentally alert.

Transition from IV to SubQ insulin: After resolution of hyperosmolar hyperglycemic state, supplement IV insulin with SubQ insulin as needed until the patient is able to eat and transition fully to a SubQ insulin regimen. An overlap of ~1 to 2 hours between discontinuation of IV insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels; for basal insulin analogues (eg, degludec, detemir, glargine), may consider an overlap of 3 to 4 hours due to their delayed onset of action (Fayfman 2017).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

The general objective of insulin replacement therapy is to approximate the physiologic pattern of insulin secretion. This requires a basal level of insulin throughout the day, supplemented by additional insulin at mealtimes. Since combinations using different types of insulins are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. The frequency of doses and monitoring must be individualized in consideration of the patient's ability to manage therapy.

Diabetes mellitus, type 1: SubQ: Infants (Limited data available), Children, and Adolescents: Note: Insulin regimens should be individualized to achieve glycemic goals without causing hypoglycemia. Multiple daily doses or continuous subcutaneous infusion guided by blood glucose monitoring are the standard of diabetes care. The daily doses presented are expressed as the total units/kg/day of all insulin formulations combined.

General insulin dosing (off-label):

Initial dose: SubQ: 0.2 to 0.6 units/kg/day in divided doses. Conservative initial doses of 0.2 to 0.4 units/kg/day are often recommended to avoid the potential for hypoglycemia.

Usual maintenance range: 0.5 to 1 unit/kg/day in divided doses; doses must be individualized; however an estimate can be determined based on phase of diabetes and level of maturity (ISPAD [Danne 2014])

Partial remission phase (Honeymoon phase): <0.5 units/kg/day

Prepubertal children (not in partial remission): 0.7 to 1 units/kg/day

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1.2 unit/kg/day and in some cases up to 2 units/kg/day

Division of daily insulin requirement ("conventional therapy"): Generally, 50% to 75% of the daily insulin dose is given as an intermediate- or long-acting form of insulin (in 1 to 2 daily injections). The remaining portion of the 24-hour insulin requirement is divided and administered as either regular insulin or a rapid-acting form of insulin at the same time before breakfast and dinner.

Division of daily insulin requirement ("intensive therapy"): Basal insulin delivery with 1 or 2 doses of intermediate- or long-acting insulin formulations superimposed with doses of rapid- or very rapid-acting insulin formulations 3 or more times daily.

Dosage adjustment: Dosage must be titrated to achieve glucose control and avoid hypoglycemia. Since combinations of agents are frequently used, dosage adjustment must address the individual component of the insulin regimen which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component.

Continuous SubQ insulin infusion (insulin pump): Using an appropriate rapid-acting insulin formulation, consists of a combination of a "basal" continuous insulin infusion rate with preprogrammed, premeal bolus doses which are patient controlled. When converting from multiple daily SubQ doses of maintenance insulin, it is advisable to reduce the basal rate to less than the equivalent of the total daily units of longer acting insulin (eg, NPH). Divide the total number of units by 24 to get the basal rate in units/hour. Do not include the total units of regular insulin or other rapid-acting insulin formulations in this calculation. The same premeal regular insulin dosage may be used.

Diabetes mellitus, type 2: Children ≥10 years and Adolescents: SubQ: The goal of therapy is to achieve an HbA1c <6.5% as quickly as possible using the safe titration of medications. Initial therapy in metabolically unstable patients (eg, plasma glucose ≥ 250 mg/dL, HbA1c >9% and symptoms excluding acidosis) may include once daily intermediate-acting insulin or basal insulin in combination with lifestyle changes and metformin. In patients who fail to achieve glycemic goals with metformin and basal insulin, may consider initiating prandial insulin (regular insulin or rapid acting insulin) and titrate to achieve goals. Once initial goal reached, insulin should be slowly tapered and the patient transitioned to lowest effective doses or metformin monotherapy if able (AAP [Copeland 2013]; ISPAD [Zeitler 2014]). Note: Patients who are ketotic or present with ketoacidosis require aggressive management as indicated.

Diabetic ketoacidosis (DKA) (off-label use): Infants, Children, and Adolescents: Note: Only IV regular insulin should be used for treatment of DKA; the rare exception where the use of SubQ rapid-acting insulin analogs (eg, aspart, lispro) may be appropriate is for patients with uncomplicated DKA in whom peripheral circulation is adequate and continuous IV regular insulin administration is not possible. Treatment should continue until resolution of acid-base abnormalities (eg, pH >7.3, serum HCO3 >15 mEq/L, and/or closure of anion gap); serum glucose is not a direct indicator of these abnormalities, and may decrease more rapidly than correction of the metabolic abnormalities. As part of overall DKA management, dextrose should be added to IV fluids to prevent hypoglycemia, usually once serum glucose is between 250 to 300 mg/dL but it may be required sooner if serum glucose has decreased precipitously. Generally, only dextrose 5% is necessary and is added to NS or 1/2NS; however, dextrose 10% or 12.5% may be necessary in some cases (ADA [Wolfsdorf 2006]; ISPAD [Wolfsdorf 2014]). Refer to institution-specific protocols where appropriate.

Continuous IV infusion:

Initial: 0.05 to 0.1 units/kg/hour; continue the rate at 0.05 to 0.1 units/kg/hour if tolerated until resolution of ketoacidosis (pH >7.3; bicarbonate >15 mEq/L and/or closure of anion gap); Note: Some patients (eg, some young children with DKA, or older children with established diabetes) may have marked sensitivity to insulin requiring lower infusion rates; these lower infusion rates should only be used provided that resolution of the acidosis continues (ADA [Wolfsdorf 2006]; ISPAD [Wolfsdorf 2014]).

After resolution of DKA: Once ketoacidosis has resolved and oral intake is tolerated, transition to a SubQ insulin regimen. An overlap between discontinuation of IV insulin and administration of SubQ insulin is recommended to ensure adequate plasma insulin levels; timing of SubQ insulin administration prior to infusion discontinuation is dependent on type of insulin used; for SubQ regular insulin: 1 to 2 hours, or for rapid-acting insulin: 15 to 30 minutes (ISPAD [Wolfsdorf 2014]).

Hyperkalemia: Limited data available: Infants, Children, and Adolescents: IV: 0.1 unit/kg with 400 mg/kg of glucose; usual ratio of combination therapy of insulin to glucose is 1 unit of insulin for every 4 g of glucose (Hegenbarth 2008). An alternate approach is glucose 1 g/kg followed by 0.2 units of insulin/g of glucose administered over 15 to 30 minutes then infused continuously as a similar amount per hour (Fuhrman 2011). In adults, the usual dose is 10 units of insulin mixed with 25 g of dextrose (50 mL of D50W) administered over 15 to 30 minutes (ACLS [Vanden Hoek 2010]).

Hyperosmolar hyperglycemic state (HHS): Limited data available: Children and Adolescents: Note: Only regular IV insulin should be used. Insulin administration should be initiated when serum glucose concentration is no longer declining at a rate ≥50 mg/dL per hour with fluid administration alone; earlier initiation may be required in patients with severe ketosis and acidosis. Infusion should continue until reversal of mental status changes and hyperosmolality. Serum glucose is not a direct indicator of these abnormalities, and may decrease more rapidly than correction of the metabolic abnormalities. Refer to institution-specific protocols where appropriate.

Continuous IV infusion: Initial: 0.025 to 0.05 units/kg/hour; titrate dose to achieve a decrease in serum glucose concentration at a rate of 50 to 75 mg/dL per hour; higher rates of decline may be required in some patients; however, if rate of decline exceeds 100 mg/dL per hour discontinue infusion (ISPAD [Wolfsdorf 2014]; Zeitler 2011)

Dosing: Renal Impairment

Insulin requirements are reduced due to changes in insulin clearance or metabolism. There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended (Aronoff 2007):

SubQ, IV: Adults:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 10 to 50 mL/minute: Administer at 75% of normal dose and monitor glucose closely.

CrCl <10 mL/minute: Administer at 50% of normal dose and monitor glucose closely.

Hemodialysis: Because of a large molecular weight (6000 daltons), insulin is not significantly removed by hemodialysis; supplemental dose is not necessary

Peritoneal dialysis: Because of a large molecular weight (6000 daltons), insulin is not significantly removed by peritoneal dialysis; supplemental dose is not necessary

Continuous renal replacement therapy: Administer 75% of normal dose and monitor glucose closely; supplemental dose is not necessary

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; dosage requirements may be reduced and patients may require more frequent dose adjustment and glucose monitoring.

Reconstitution

For SubQ administration: Humulin R U-100: May be diluted with manufacturer’s sterile diluent down to a concentration of 10 units/mL (U-10) (data on file [Eli Lilly 2018]).

For IV infusion:

Humulin R U-100: May be diluted in NS or D5W to concentrations of 0.1 to 1 unit/mL.

Novolin R: May be diluted in NS, D5W, or D10W with 40 mEq/L potassium chloride at concentrations of 0.05 to 1 unit/mL.

Administration

SubQ administration: Do not use if solution is viscous or cloudy; use only if clear and colorless. Regular insulin should be administered ~30 minutes before a meal. Cold injections should be avoided. SubQ administration is usually made into the thighs, arms, buttocks, or abdomen; rotate injection sites within the same region to avoid lipodystrophy.

U-100 regular insulin: When mixing U-100 regular insulin with other preparations of insulin, regular insulin should be drawn into syringe first.

FlexPen: Prime the needle before each injection with 2 units of insulin. Once injected, hold the FlexPen device in the skin for a count of 6 after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered.

U-500 regular insulin (concentrated): Do not dilute or mix U-500 regular insulin.

Vials: U-500 regular insulin vials are to be used only in conjunction with a dedicated U-500 insulin syringe; dosage conversion is not required with the U-500 syringe. Only in cases where the U-500 insulin syringe is not available, a U-100 insulin syringe or a tuberculin syringe may be necessary. When using a U-100 syringe or a tuberculin syringe to deliver Humulin R U-500 (from vial), a conversion step is required to ensure the correct amount of Humulin R U-500 is drawn up in the syringe. To avoid dosing errors when using a U-100 insulin syringe, the prescribed dose should be written in actual insulin units and as unit markings on the U-100 insulin syringe (eg , Humulin R U-500 50 units = 10 units on a U-100 insulin syringe). To avoid dosing errors when using a tuberculin syringe, the prescribed dose should be written in actual insulin units and as a volume (eg, Humulin R U-500 50 units = 0.1 mL on a tuberculin syringe).

KwikPen: Do not perform dose conversions when using the KwikPen; the dose window shows the number of units to be injected. Do not transfer KwikPen insulin into a syringe for administration. Prime the needle before each injection with 5 units of insulin. Once the dose is injected, hold the device in the skin for a count of 5 after the dose dial has returned to 0 units before removing the needle to ensure the full dose has been administered.

CSII: Novolin regular insulin (U-100) is not recommended for use in external SubQ insulin infusion pump due to precipitation concerns (manufacturer labeling). U-500 regular insulin is generally not recommended for use in an insulin pump but may be used in select patients under the supervision of a qualified provider (AACE [Grunberger 2010]; Endocrine Society [Peters 2016]).

IM administration: Do not administer U-500 regular insulin IM. Do not use if solution is viscous or cloudy; use only if clear and colorless. May be administered IM in selected clinical situations; close monitoring of blood glucose and serum potassium as well as medical supervision is required.

IV administration: Do not administer U-500 regular insulin or mixtures of insulin formulations IV. Do not use if solution is viscous or cloudy; use only if clear and colorless. U-100 regular insulin may be administered IV with close monitoring of blood glucose and serum potassium; appropriate medical supervision is required.

IV infusions: To minimize insulin adsorption to plastic IV tubing: Insulin loss will occur by adsorption to plastic (ie, PVC, polyethylene, polyolefin, polypropylene) IV containers and tubing (Greenwood 2012; Hirsch 1977; Hirsch 1981; Rocchio 2013; Thompson 2012). Therefore, flush the IV tubing with a priming infusion of 20 mL from the insulin infusion, whenever a new IV tubing set is added to the insulin infusion container (SCCM [Jacobi 2012]; Thompson 2012).

Note: Also refer to institution-specific protocols where appropriate.

If insulin is required prior to the availability of the insulin drip, regular insulin should be administered by IV push injection.

Because of insulin adsorption to plastic IV tubing or infusion bags, the actual amount of insulin being administered via IV infusion could be substantially less than the apparent amount. Therefore, adjustment of the IV infusion rate should be based on effect and not solely on the apparent insulin dose. The apparent dose may be used as a starting point for determining the subsequent SubQ dosing regimen (Moghissi 2009); however, the transition to SubQ administration requires continuous medical supervision, frequent monitoring of blood glucose, and careful adjustment of therapy. In addition, SubQ insulin should be given 1 to 4 hours prior to the discontinuation of IV insulin to prevent hyperglycemia (Moghissi 2009).

Dietary Considerations

Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy.

Storage

Humulin R U-100: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F) until expiration date; do not freeze; keep away from heat and sunlight. Once punctured (in use), vials may be stored for up to 31 days in the refrigerator between 2°C and 8°C (36°F to 46°F) or at room temperature of ≤30°C (≤86°F).

Humulin R U-500:

Vials: Store unopened vials (not in use) in a refrigerator (2°C to 8°C [36°F to 46°F]) until expiration date or may be stored at room temperature <30°C [86°F]) for up to 40 days. Protect from heat and light; do not freeze and do not use if the vial has been frozen. Store vials currently opened (in use) in a refrigerator (2°C to 8°C [36°F to 46°F]) or at room temperature <30°C [86°F]) and discard after 40 days. Do not shake vial.

KwikPen: Store unopened pens (not in use) in a refrigerator (2°C to 8°C [36°F to 46°F]) until expiration date or may be stored at room temperature (<30°C [86°F]) for up to 28 days. Protect from heat and light; do not freeze or use if pen has been frozen. Store in-use (opened) pens at room temperature (<30°C [86°F]) and discard pen after 28 days; do not refrigerate. For single-patient use only.

Novolin R:

Vials: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F) until product expiration date or at room temperature ≤25°C (≤77°F) for up to 42 days; do not freeze; keep away from heat and sunlight. Once punctured (in use), store vials at room temperature ≤25°C (≤77°F) for up to 42 days; refrigeration of in-use vials is not recommended.

FlexPen: Store unopened (not in use) pens in refrigerator between 2°C and 8°C (36°F to 46°F) until product expiration date or at room temperature (<30°C [86°F]) for up to 28 days; store in use (opened) pens at room temperature (<30°C [86°F]) for up to 28 days. Do not use if pen has been frozen; keep away from heat and light. For single-patient use only.

Canadian labeling (not in US labeling): All products: Unopened vials, cartridges, and pens should be stored under refrigeration between 2°C and 8°C (36°F to 46°F) until the expiration date; do not freeze; keep away from heat and sunlight. Once punctured (in use), Humulin vials, cartridges, and pens should be stored at room temperature <25°C (<77°F) for up to 4 weeks. Once punctured (in use), Novolin ge vials, cartridges, and pens may be stored for up to 1 month at room temperature <25°C (<77°F) for vials or <30°C (<86°F) for pens/cartridges; do not refrigerate.

For SubQ administration: Humulin R U-100: According to the manufacturer, insulin diluted with the manufacturer's sterile diluent in a glass vial may be stored at 30°C (86°F) for up to 14 days or at 5°C (41°F) for up to 28 days. Do not store diluted insulin in a plastic syringe. Store unused sterile diluent at room temperature; once in-use, the sterile diluent vial should be used within 28 days (data on file [Eli Lilly 2018]).

For IV infusion:

Humulin R U-100: Stable for 48 hours at room temperature or for 48 hours under refrigeration followed by 48 hours at room temperature.

Novolin R: Stable for 24 hours at room temperature

Note: After dilution of 100 units of regular human insulin (product not specified) in 100 mL of 0.9% NaCl (PVC bag), the solution is stable under refrigeration between 2°C and 8°C (36°F to 46°F) for up to 336 hours (Rocchio 2013).

Drug Interactions

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Beta-Blockers: May enhance the hypoglycemic effect of Insulins. Exceptions: Levobunolol; Metipranolol. Monitor therapy

Dipeptidyl Peptidase-IV Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Edetate CALCIUM Disodium: May enhance the hypoglycemic effect of Insulins. Monitor therapy

Edetate Disodium: May enhance the hypoglycemic effect of Insulins. Monitor therapy

Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Insulins. Management: Consider insulin dose reductions when used in combination with glucagon-like peptide-1 agonists. Avoid the use of lixisenatide in patients receiving both basal insulin and a sulfonylurea. Exceptions: Liraglutide. Consider therapy modification

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Liraglutide: May enhance the hypoglycemic effect of Insulins. Management: If liraglutide is used for the treatment of diabetes (Victoza), consider insulin dose reductions. The combination of liraglutide and insulin should be avoided if liraglutide is used exclusively for weight loss (Saxenda). Consider therapy modification

Macimorelin: Insulins may diminish the diagnostic effect of Macimorelin. Avoid combination

Metreleptin: May enhance the hypoglycemic effect of Insulins. Management: Insulin dosage adjustments (including potentially large decreases) may be required to minimize the risk for hypoglycemia with concurrent use of metreleptin. Monitor closely. Consider therapy modification

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pioglitazone: May enhance the adverse/toxic effect of Insulins. Specifically, the risk for hypoglycemia, fluid retention, and heart failure may be increased with this combination. Management: If insulin is combined with pioglitazone, dose reductions should be considered to reduce the risk of hypoglycemia. Monitor patients for fluid retention and signs/symptoms of heart failure. Consider therapy modification

Pramlintide: May enhance the hypoglycemic effect of Insulins. Management: Upon initiation of pramlintide, decrease mealtime insulin dose by 50% to reduce the risk of hypoglycemia. Monitor blood glucose frequently and individualize further insulin dose adjustments based on glycemic control. Consider therapy modification

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Rosiglitazone: Insulins may enhance the adverse/toxic effect of Rosiglitazone. Specifically, the risk of fluid retention, heart failure, and hypoglycemia may be increased with this combination. Avoid combination

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sodium-Glucose Cotransporter 2 (SLGT2) Inhibitors: May enhance the hypoglycemic effect of Insulins. Management: Consider a decrease in insulin dose when initiating therapy with a sodium-glucose cotransporter 2 inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Adverse Reactions

Frequency not always defined.

Cardiovascular: Peripheral edema

Dermatologic: Erythema at injection site, injection site pruritus

Endocrine & metabolic: Hypoglycemia, hypokalemia, weight gain

Hypersensitivity: Anaphylaxis, hypersensitivity, hypersensitivity reaction

Local: Hypertrophy at injection site, lipoatrophy at injection site

Warnings/Precautions

Concerns related to adverse effects:

• Glycemic control: Hyper- or hypoglycemia may result from changes in insulin strength, manufacturer, type, and/or administration method. The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from changes in meal pattern (eg, macronutrient content, timing of meals), changes in the level of physical activity, increased work or exercise without eating, or changes to coadministered medications. Use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from hypoglycemia. Patients with renal or hepatic impairment may be at a higher risk. Symptoms differ in patients and may change over time in the same patient; awareness may be less pronounced in those with long-standing diabetes, diabetic nerve disease, patients taking beta-blockers, or in those who experience recurrent hypoglycemia. Profound and prolonged episodes of hypoglycemia may result in convulsions, unconsciousness, temporary or permanent brain damage, or even death. Insulin requirements may be altered during illness, emotional disturbances, or other stressors. Instruct patients to use caution with ethanol; may increase risk of hypoglycemia.

• Hypersensitivity: Severe, life-threatening, generalized allergic reactions, including anaphylaxis, may occur. If hypersensitivity reactions occur, discontinue therapy, treat the patient with supportive care and monitor until signs and symptoms resolve.

• Hypokalemia: Insulin (especially IV insulin) causes a shift of potassium from the extracellular space to the intracellular space, possibly producing hypokalemia. If left untreated, hypokalemia may result in respiratory paralysis, ventricular arrhythmia and even death. Use with caution in patients at risk for hypokalemia (eg, loop diuretic use). Monitor serum potassium frequently with IV insulin use and supplement potassium when necessary.

Disease-related concerns:

• Cardiac disease: Concurrent use with peroxisome proliferator-activated receptor (PPAR)-gamma agonists, including thiazolidinediones (TZDs) may cause dose-related fluid retention and lead to or exacerbate heart failure, particularly when used in combination with insulin. If PPAR-gamma agonists are prescribed, monitor for signs and symptoms of heart failure. If heart failure develops, consider PPAR-gamma agonist dosage reduction or therapy discontinuation.

• Hepatic impairment: Use with caution in patients with hepatic impairment; increased risk of hypoglycemia. Dosage requirements may be reduced and patients may require more frequent dose adjustment and glucose monitoring.

• Renal impairment: Use with caution in patients with renal impairment; increased risk of hypoglycemia. Dosage requirements may be reduced and patients may require more frequent dose adjustment and glucose monitoring.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Hospitalized patients with diabetes: Exclusive use of a sliding scale insulin regimen in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion has been shown to best achieve glycemic targets. In noncritically ill patients with either poor oral intake or taking nothing by mouth, basal insulin or basal plus bolus is preferred. In noncritically ill patients with adequate nutritional intake, a combination of basal insulin, nutritional, and correction components is preferred. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia. A blood glucose value <70 mg/dL should prompt a treatment regimen review and change, if necessary, to prevent further hypoglycemia (ADA 2018).

Dosage form specific issues:

• Multiple-dose injection pens: According to the Centers for Disease Control and Prevention (CDC), pen-shaped injection devices should never be used for more than one person (even when the needle is changed) because of the risk of infection. The injection device should be clearly labeled with individual patient information to ensure that the correct pen is used (CDC 2012).

• Product variation: Human insulin differs from animal-source insulin. Any change of insulin should be made cautiously; changing manufacturers, type, and/or method of manufacture may result in the need for a change of dosage. Verify product label prior to administration to prevent medication errors.

• U-500 regular insulin: U-500 regular insulin is a concentrated insulin formulation which contains 500 units of insulin per mL and is intended for subQ administration only; do not administer IV or IM. U-500 regular insulin is generally not recommended for use in an insulin pump, but may be used in select patients under the supervision of a qualified provider (AACE [Grunberger 2010]; Endocrine Society [Peters 2016]). Prescribe only to patients who require more than 200 units of insulin per day. Doses from a U-500 regular insulin vial should be drawn up only with a dedicated U-500 insulin syringe. Do not mix or dilute U-500 regular insulin with other insulin formulations. Insulin U-500 also has a delayed onset and longer duration of action compared to regular insulin U-100, and has both prandial and basal properties (ADA 2018). Do not perform dose conversions when using the KwikPen, the dose window shows the number of units to be injected. Do not transfer insulin from the KwikPen to a syringe for administration.

Other warnings/precautions:

• IM administration: Regular insulin U-100 (ie, 100 units/mL) may be administered IM in selected clinical situations to control hyperglycemia (eg, DKA); close monitoring of blood glucose and serum potassium as well as medical supervision is required. Do not administer U-500 regular insulin IM.

• IV administration: Regular insulin U-100 (ie, 100 units/mL) may be administered IV in selected clinical situations (eg, DKA, hyperkalemia); close monitoring of blood glucose and serum potassium as well as medical supervision is required. Do not administer U-500 regular insulin IV.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

Monitoring Parameters

Critically ill patients receiving insulin infusion: Blood glucose every 1 to 2 hours. Note: Every 4 hour blood glucose monitoring is not recommended unless a low hypoglycemia rate is demonstrated with the insulin protocol used. Arterial or venous whole blood sampling is recommended for patients in shock, on vasopressor therapy, or with severe edema, and when on a prolonged insulin infusion (SCCM [Jacobi 2012]).

Diabetes mellitus: Plasma glucose, electrolytes, HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2018]); renal function, hepatic function, weight

DKA/HHS: Serum electrolytes, glucose, BUN, creatinine, osmolality, venous pH (repeat arterial blood gases are generally unnecessary), anion gap, urine output, urinalysis, mental status

Hyperkalemia: Serum potassium and glucose must be closely monitored to avoid hypokalemia, rebound hyperkalemia, and hypoglycemia.

Pregnancy Considerations

Animal reproduction studies have not been conducted. Exogenous insulin bound to anti-insulin antibodies can be detected in cord blood (Menon 1990).

In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2018; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2018; Blumer 2013; Lambert 2013).

Insulin requirements tend to fall during the first trimester of pregnancy and increase in the later trimesters, peaking at 28 to 32 weeks' gestation. Following delivery, insulin requirements decrease rapidly (ACOG 2005).

Insulin therapy is the preferred treatment of type 1 and type 2 diabetes in pregnant women, as well as GDM when pharmacologic therapy is needed (ACOG 190 2018; ADA 2018). Rapid acting insulins may be preferred over regular human insulin in women trying to conceive (Blumer 2013); however, there is no need to switch a pregnant woman who is well-controlled on injectable human insulin to a short acting analogue (Lambert 2013). Regular insulin is used intravenously for glycemic control during labor.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience weight gain. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), anxiety, severe injection site irritation, vision changes, chills, severe dizziness, passing out, mood changes, seizures, burning or numbness feeling, slurred speech, swelling of arms or legs, or change in skin to thick or thin at injection site (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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