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Insulin Regular

Pronunciation

Pronunciation

(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, phenol]

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]

HumuLIN R U-500 KwikPen: 500 units/mL (3 mL)

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: To improve glycemic control in adult and pediatric patients with diabetes mellitus requiring daily doses of more than 200 units of insulin per day

Use: Unlabeled

Injection: Adjunct of parenteral nutrition; diabetic ketoacidosis (DKA); hyperglycemia during critical illness; hyperkalemia; hyperosmolar hyperglycemic state (HHS)

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

Diabetes mellitus: SubQ: Note: Insulin requirements vary dramatically between patients and therapy requires dosage adjustments with careful medical supervision. Specific formulations may require distinct administration procedures; please see individual agents.

Diabetes mellitus, type 1:

General insulin dosing:

Note: Multiple daily doses or continuous subcutaneous infusions guided by blood glucose monitoring are the standard of diabetes care. Combinations of insulin formulations are commonly used. The daily doses presented below are expressed as the total units/kg/day of all insulin formulations combined.

Initial total insulin dose: 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. A rapid-acting insulin may be the only insulin formulation used initially.

Usual maintenance range: 0.5 to 1 units/kg/day in divided doses. An estimate of anticipated needs may be based on body weight and/or activity factors as follows:

Nonobese: 0.4 to 0.6 units/kg/day

Obese: 0.8 to 1.2 units/kg/day

Pubescent Children and Adolescents: During puberty, requirements may substantially increase to >1 unit/kg/day and in some cases up to 2 units/kg/day (IDF/ISPAD 2011).

Division of daily insulin requirement (“conventional therapy”): Generally, 50% to 75% of the total daily dose (TDD) is given as an intermediate- or long-acting form of insulin (in 1 to 2 daily injections). The remaining portion of the TDD is then divided and administered before or at mealtimes (depending on the formulation) as a rapid-acting (eg, insulin aspart) or short-acting form of insulin. Some patients may benefit from the use of CSII which delivers rapid-acting insulin (insulin aspart) as a continuous infusion throughout the day and as boluses at mealtimes via an external pump device.

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 short- or rapid-acting insulin (eg, insulin aspart) formulations 3 or more times daily.

Adjustment of dose: 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 which most directly influences the blood glucose value in question, based on the known onset and duration of the insulin component. Treatment and monitoring regimens must be individualized. Also see Additional Information or Pharmacotherapy Pearls.

Continuous SubQ insulin infusion (insulin pump): A combination of a "basal" continuous insulin infusion rate with preprogrammed, premeal bolus doses that 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 the 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:

General considerations for insulin use in type 2 diabetes:

Timing of initiation: The goal of therapy is to achieve an HbA1c <7%. According to a position statement by the ADA and European Association for the Study of Diabetes (EASD), dual therapy (metformin + a second antihyperglycemic agent) is recommended in patients with type 2 diabetes who fail to achieve glycemic goals after ~3 months with lifestyle interventions and metformin monotherapy (unless contraindications to metformin exist). Preference is not given for adding insulin or a noninsulin agent as the second antihyperglycemic agent (drug choice should be individualized based on patient characteristics). However, insulin should be considered as part of a combination regimen when hyperglycemia is severe, particularly if patient is symptomatic or has catabolic features (eg, weight loss, ketosis). If insulin is selected, the addition of basal insulin (ie, a long-acting insulin such as glargine or detemir [not insulin regular]) is recommended. If HbA1c target not achieved after ~3 months of dual therapy, may proceed to triple therapy (Inzucchi 2015).

Intensification of therapy: If HbA1c target has not been met, despite titrating basal insulin (ie, long-acting insulin) to provide acceptable fasting blood glucose concentrations, intensification of therapy should be considered to cover postprandial glucose excursions. Options include: adding a mealtime insulin (1 to 3 injections of a rapid-acting insulin analog [lispro, aspart, glulisine]) or adding a GLP-1 receptor agonist (eg, exenatide, liraglutide). Alternatively, although less studied, may transition from basal insulin (ie, long-acting insulin) to a twice daily premixed (or biphasic) insulin analog (70/30 aspart mix, 75/25 or 50/50 lispro mix) (Inzucchi 2015).

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 (DKA) (off-label use): Only IV regular insulin should be used for severe DKA (Kitabchi 2009). Treatment should continue until reversal of acid-base derangement/ketonemia. 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.

Adults <20 years (Kitabchi 2004):

IV infusion: 0.1 units/kg/hour

Adjustment: If serum glucose does not fall by 50 mg/dL in the first hour, check hydration status; if acceptable, double insulin dose hourly until glucose levels fall at rate of 50 to 75 mg/dL per hour. Once serum glucose reaches 250 mg/dL, decrease dose to 0.05 to 0.1 units/kg/hour; dextrose-containing IV fluids should be administered to maintain serum glucose between 150 to 250 mg/dL until the acidosis clears. After resolution of DKA, 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.

SubQ, IM (Note: Only use the SubQ and IM route if IV infusion access is unavailable): 0.1 to 0.3 units/kg SubQ bolus, followed by 0.1 units/kg given every hour SubQ or IM or 0.15 to 0.2 units/kg every 2 hours SubQ; continue until acidosis clears, then decrease to 0.05 units/kg given every hour until SubQ replacement dosing can be initiated (Kitabchi 2004; Wolfsdorf 2007)

Adults ≥20 years (Kitabchi 2009):

IV:

Bolus: 0.1 units/kg (optional)

Infusion: 0.1 to 0.14 units/kg/hour. Note: If no IV bolus was administered, patients should receive a continuous infusion of 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 70 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; dextrose-containing IV fluids should be administered to maintain serum glucose between 150 to 250 mg/dL until the acidosis clears. After resolution of DKA, 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.

SubQ, IM: The following dosing regimen from the 2004 ADA position statement recommends regular insulin (Kitabchi 2004):

Bolus: 0.4 units/kg; Note: Give half of the dose (0.2 units/kg) as an IV bolus and half of the dose (0.2 units/kg) as SubQ or IM

Intermittent: 0.1 units/kg given every hour SubQ or IM

Adjustment: If serum glucose does not fall by 50 to 70 mg/dL in the first hour, administer 10 units hourly by IV bolus until glucose levels fall at a rate of 50 to 70 mg/dL per hour. Once serum glucose reaches 250 mg/dL, decrease dose to 5 to 10 units SubQ every 2 hours; dextrose-containing IV fluids should be administered to maintain serum glucose between 150 to 250 mg/dL until the acidosis clears.

Gestational diabetes mellitus (off-label use): SubQ: Insulin therapy should be considered when medical nutrition therapy has not achieved GDM glycemic goals (fasting plasma glucose: <95 mg/dL; 1-hour postprandial levels: <130 to 140 mg/dL; 2-hour postprandial levels: <120 mg/dL); dose and timing of administration should be based on frequent monitoring of plasma glucose levels (ACOG 2001; ADA 2004). Human insulin may be preferred (ADA 2004); however, rapid-acting insulin analogues may also be considered (ACOG 2001).

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 (Dellinger 2013).

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 (ACLS 2010); alternatively, 50 mL D50W over 5 minutes followed by 10 units regular insulin IV push over seconds may be administered in the setting of imminent cardiac arrest. In patients with ongoing cardiac arrest (eg, PEA with presumed hyperkalemia), administration of D50W over <5 minutes is routine. Effects on potassium are temporary. As appropriate, consider methods of enhancing potassium removal/excretion.

Hyperosmolar hyperglycemic state (HHS) (off-label use): 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.

Adults <20 years (Kitabchi 2004):

IV:

Infusion: 0.1 units/kg/hour

Adjustment: If serum glucose does not fall by 50 mg/dL in the first hour, check hydration status; if acceptable, double insulin dose hourly until glucose levels fall at rate of 50 to 75 mg/dL per hour. Once serum glucose reaches 300 mg/dL, decrease dose to 0.05 to 0.1 units/kg/hour; dextrose-containing IV fluids should be administered to maintain serum glucose between 250 to 300 mg/dL until hyperosmolality clears and mental status returns to normal. After resolution of HHS, 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.

SubQ, IM (Note: Only use the SubQ and IM route if IV infusion access is unavailable): 0.1 to 0.3 units/kg SubQ bolus, followed by 0.1 units/kg given every hour SubQ or IM or 0.15 to 0.2 units/kg every 2 hours SubQ; continue until resolution of hyperosmolality, then decrease to 0.05 units/kg given every hour until SubQ replacement dosing can be initiated (Kitabchi 2004; Wolfsdorf 2007)

Adults ≥20 years (Kitabchi 2009):

IV:

Bolus: 0.1 units/kg bolus (optional)

Infusion: 0.1 to 0.14 units/kg/hour. Note: If no IV bolus was administered, patients should receive a continuous infusion of 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 70 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; dextrose-containing IV fluids should be administered to maintain serum glucose between 200 to 300 mg/dL until the patient is mentally alert. After resolution of HHS, 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.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Diabetes mellitus, type 1: SubQ: Refer to adult dosing.

Diabetic ketoacidosis (DKA) (off-label use): Only IV regular insulin should be used for severe DKA; use of SubQ rapid-acting insulin analogs (eg, aspart, lispro) may be appropriate for mild-moderate DKA (Kitabchi 2009). Treatment should continue until reversal of acid-base derangement/ketonemia. 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: (Kitabchi 2004):

Infusion: 0.1 units/kg/hour

Adjustment: If serum glucose does not fall by 50 mg/dL in the first hour, check hydration status; if acceptable, double insulin dose hourly until glucose levels fall at rate of 50 to 75 mg/dL per hour. Once serum glucose reaches 250 mg/dL, decrease dose to 0.05 to 0.1 units/kg/hour; dextrose-containing IV fluids should be administered to maintain serum glucose between 150 to 250 mg/dL until the acidosis clears. After resolution of DKA, 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.

SubQ, IM (Note: Only use the SubQ and IM route if IV infusion access is unavailable): 0.1 to 0.3 units/kg SubQ bolus, followed by 0.1 units/kg given every hour SubQ or IM or 0.15 to 0.2 units/kg every 2 hours SubQ; continue until acidosis clears, then decrease to 0.05 units/kg given every hour until SubQ replacement dosing can be initiated (Kitabchi 2004; Wolfsdorf 2007)

Hyperkalemia, moderate-to-severe (off-label use): IV: 0.1 units/kg regular insulin with dextrose 400 mg/kg infused over 15 to 30 minutes; ratio of ~1 unit of insulin to every 4 g of dextrose (Hegenbarth 2008). Note: Dextrose monotherapy may be sufficient to correct hyperkalemia.

Hyperosmolar hyperglycemic state (HHS) (off-label use): 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 (Kitabchi 2004):

Infusion: 0.1 units/kg/hour

Adjustment: If serum glucose does not fall by 50 mg/dL in the first hour, check hydration status; if acceptable, double insulin dose hourly until glucose levels fall at rate of 50 to 75 mg/dL per hour. Once serum glucose reaches 300 mg/dL, decrease dose to 0.05 to 0.1 units/kg/hour; dextrose-containing IV fluids should be administered to maintain serum glucose between 250 to 300 mg/dL until hyperosmolality clears and mental status returns to normal. After resolution of HHS, 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.

SubQ, IM (Note: Only use the SubQ and IM route if IV infusion access is unavailable): 0.1 to 0.3 units/kg SubQ bolus, followed by 0.1 units/kg given every hour SubQ or IM or 0.15 to 0.2 units/kg every 2 hours SubQ; continue until resolution of hyperosmolality, then decrease to 0.05 units/kg given every hour until SubQ replacement dosing can be initiated (Kitabchi 2004; Wolfsdorf 2007)

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 25% to 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 the universal diluent, Sterile Diluent for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin R U-500, to a concentration of 10 units/mL (U-10) or 50 units/mL (U-50).

Novolin R: Insulin Diluting Medium for NovoLog is not intended for use with Novolin R or any insulin product other than insulin aspart.

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 within 30 to 60 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. When mixing regular insulin with other preparations of insulin, regular insulin should be drawn into syringe first. Do not dilute or mix U-500 regular insulin. Regular insulin is not recommended for use in external SubQ insulin infusion pump. 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 ). 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.

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 IV. Do not use if solution is viscous or cloudy; use only if clear and colorless. May be administered IV with close monitoring of blood glucose and serum potassium; appropriate medical supervision is required. If possible, avoid IV bolus administration in pediatric patients with DKA; may increase risk of cerebral edema. Do not administer mixtures of insulin formulations IV.

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.

Compatibility

Stable in D5W and NS. Note: A universal sterile diluent, Sterile Diluent for Humalog, Humulin N, Humulin R U-100, Humulin 70/30, and Humulin R U-500, is available from the manufacturer for SubQ administration.

Y-site administration: Incompatible with dopamine, micafungin, nafcillin, nesiritide, ranitidine.

Compatibility in syringe: Incompatible: with insulin aspart, insulin detemir, insulin glargine, insulin glulisine, insulin lispro.

Storage

Humulin R: Store unopened vials in refrigerator between 2°C and 8°C (36°F to 46°F); 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: 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 (this includes any days stored at room temperature prior to opening vial); refrigeration of in-use vials is not recommended.

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, diluted insulin should be stored at 30°C (86°F) and used within 14 days or at 5°C (41°F) and used within 28 days.

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 Insulin. Exceptions: Levobunolol; Metipranolol. Monitor therapy

DPP-IV Inhibitors: May enhance the hypoglycemic effect of Insulin. 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 Insulin. Monitor therapy

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

GLP-1 Agonists: May enhance the hypoglycemic effect of Insulin. 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

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 Insulin. 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

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

Metreleptin: May enhance the hypoglycemic effect of Insulin. 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

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

Pioglitazone: May enhance the adverse/toxic effect of Insulin. 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 Insulin. 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

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics 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

Rosiglitazone: Insulin 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

SGLT2 Inhibitors: May enhance the hypoglycemic effect of Insulin. 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:

• 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.

• Hypoglycemia: 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 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.

• 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 to manage persistent hyperglycemia in the hospital is discouraged. An effective insulin regimen will achieve the goal glucose range without the risk of severe hypoglycemia (ADA 2016b).

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.

• U-500 regular insulin: U-500 regular insulin is a concentrated insulin formulation which contains 500 units of insulin per mL; for SubQ administration only using a U-100 insulin syringe or tuberculin syringe; not for IV or IM administration or use in an insulin pump. Prescribe only to patients who require more than 200 units of insulin per day. 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, 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, 50 units [0.1 mL]). Do not mix or dilute U-500 regular insulin with other insulin formulations. 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:

• Appropriate use: Diabetes mellitus: The general objective of exogenous insulin therapy is to approximate the physiologic pattern of insulin secretion which is characterized by two distinct phases. Phase 1 insulin secretion suppresses hepatic glucose production and phase 2 insulin secretion occurs in response to carbohydrate ingestion; therefore, exogenous insulin therapy may consist of basal insulin (eg, intermediate- or long-acting insulin via continuous subcutaneous insulin infusion [CSII]) and/or preprandial insulin (eg, short- or rapid-acting insulin) (see Related Information: Insulin Products). Patients with type 1 diabetes do not produce endogenous insulin; therefore, these patients require both basal and preprandial insulin administration. Patients with type 2 diabetes retain some beta-cell function in the early stages of their disease; however, as the disease progresses, phase 1 insulin secretion may become completely impaired and phase 2 insulin secretion becomes delayed and/or inadequate in response to meals. Therefore, patients with type 2 diabetes may be treated with oral antidiabetic agents, basal insulin, and/or preprandial insulin depending on the stage of disease and current glycemic control. Since treatment regimens often consist of multiple agents, dosage adjustments must address the specific phase of insulin release that is primarily contributing to the patient’s impaired glycemic control. Treatment and monitoring regimens must be individualized.

• 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 2016c])

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 Risk Factor

B

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 2016a; Kitzmiller 2008; 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 (ACOG 2013; ADA 2016a; Blumer 2013; Kitzmiller 2008; Lambert 2013). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (ADA 2016a; Kitzmiller 2008).

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

Rapid-acting insulins, such as insulin aspart or insulin lispro 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.

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