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Insulin Aspart

Pronunciation

(IN soo lin AS part)

Index Terms

  • Aspart Insulin
  • Fiasp

Dosage Forms

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

Solution, Subcutaneous:

Fiasp: 100 units/mL (10 mL) [contains metacresol, phenol]

NovoLOG: 100 units/mL (10 mL) [contains metacresol, phenol]

Solution Cartridge, Subcutaneous:

NovoLOG PenFill: 100 units/mL (3 mL) [contains metacresol, phenol]

Solution Pen-injector, Subcutaneous:

Fiasp FlexTouch: 100 units/mL (3 mL) [contains metacresol, phenol]

NovoLOG FlexPen: 100 units/mL (3 mL) [contains metacresol, phenol]

Brand Names: U.S.

  • Fiasp
  • Fiasp FlexTouch
  • NovoLOG
  • NovoLOG FlexPen
  • NovoLOG PenFill

Pharmacologic Category

  • Insulin, Rapid-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; it 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. Insulin aspart differs from human insulin by containing aspartic acid at position B28 in comparison to the proline found in human insulin. Insulins are categorized based on the onset, peak, and duration of effect (eg, rapid-, short-, intermediate-, and long-acting insulin). Insulin aspart is a rapid-acting insulin analog.

Excretion

Urine; Clearance: Adults: 1.22 L/hour/kg

Onset of Action

~0.2 to 0.3 hours; Peak effect: 1 to 3 hours (Novolog); ~1.5 to 2.22 hours (Fiasp)

Time to Peak

Plasma: 40 to 50 minutes (Novolog); ~63 minutes (Fiasp)

Duration of Action

3 to 5 hours (Novolog); ~5 to 7 hours (Fiasp)

Half-Life Elimination

SubQ: 81 minutes (Novolog); 1.1 hours (Fiasp)

Protein Binding

<10%

Special Populations Note

Obesity: Novolog clearance is reduced 28% in patients with a BMI >32 kg/m2 compared with patients with a BMI l<23 kg/m2.

Use: Labeled Indications

Diabetes mellitus, types 1 and 2: Treatment of type 1 diabetes mellitus (insulin dependent, IDDM) and type 2 diabetes mellitus (noninsulin dependent, NIDDM) to improve glycemic control

Off Label Uses

Diabetic ketoacidosis (mild-to-moderate)

Data from a prospective, randomized open label trial in a limited number of patients with uncomplicated diabetic ketoacidosis comparing the use of subcutaneous insulin aspart to a standard low-dose IV infusion protocol of regular insulin supports the use of insulin aspart in the treatment of mild-to-moderate diabetic ketoacidosis [Umpierrez 2004]. Additional trials may be necessary to further define the role of insulin aspart in the management of this condition.

Based on a consensus statement from the American Diabetic Association for the treatment of patients with hyperglycemic crises in adult patients with diabetes, the use of rapid-acting insulin analogues (eg, insulin aspart) is an effective alternative to intravenous regular insulin in the management of diabetic ketoacidosis.

Gestational diabetes mellitus

Based on the American College of Obstetricians and Gynecologists Practice Bulletin for the management of gestational diabetes mellitus (GDM) and the American Diabetes Association Standards of Medical Care for the management of diabetes in pregnancy, insulin may be used to treat GDM when nutrition and exercise therapy are not effective. Insulin aspart is an insulin analogue that has been used in pregnancy, has a more rapid onset of action than regular insulin, and may be useful in improving postprandial glucose concentrations [ACOG 2013], [ADA 2017c]. The Endocrine Society Clinical Practice Guideline on Diabetes and Pregnancy recommends the use of rapid-acting insulin analogs lispro and aspart in preference to regular insulin in pregnant women with diabetes [Blumer 2013].

Hyperglycemia during critical illness

Data from two prospective, randomized, controlled trials in the ICU population supports the use of insulin 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 aspart 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.

Additional Off-Label Uses

Hyperosmolar hyperglycemic state (HHS) (mild-to-moderate)

Contraindications

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

Dosing: Adult

Note: Insulin aspart is a rapid-acting insulin analog which is normally administered SubQ as a premeal component of the insulin regimen or as a continuous SubQ infusion and should be used with intermediate- or long-acting insulin. When compared to insulin regular, insulin aspart has a more rapid onset and shorter duration of activity. In carefully controlled clinical settings with close medical supervision and monitoring of blood glucose and potassium, insulin aspart may also be administered IV. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision.

Diabetes mellitus, type 1:

General insulin dosing (off-label):

Type 1: SubQ: 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

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, lispro, aspart, glulisine) or short-acting (regular) form of insulin. Some patients may benefit from the use of CSII which delivers rapid-acting insulin 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-acting (regular) or rapid-acting insulin (eg, lispro, aspart, glulisine) 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. Treatment and monitoring regimens must be individualized.

Continuous SubQ insulin infusion (insulin pump): 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 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: SubQ:

Off-label:

Initial: 4 units or 0.1 unit/kg or 10% of the basal insulin dose; insulin aspart (ie, a rapid acting insulin) is administered before the largest meal of the day and is usually given in addition to a regimen that includes basal insulin (ie, a long-acting insulin such as glargine, degludec, or detemir) and metformin +/- other noninsulin agents. If HbA1c is still not controlled despite titrations to reach glycemic targets, one option is to advance to 'basal-bolus' (ie, insulin aspart administered before ≥2 meals per day) in addition to basal insulin and usually given in addition to metformin +/- other noninsulin agent (ADA 2017f).

Dosage adjustment:

To reach self-monitoring glucose target: Adjust dose by 10 to 15% or 1 to 2 units; may adjust at weekly or twice weekly intervals (ADA 2017f)

For hypoglycemia: If no clear reason for hypoglycemia, decrease dose by 2 to 4 units or by 10 to 20% (ADA 2017f)

General considerations for insulin use in type 2 diabetes (off-label):

Timing of initiation: Dual therapy (metformin + a second antihyperglycemic agent) and then triple therapy (metformin + two antihyperglycemic agents) is recommended in patients who fail to achieve glycemic goals after ~3 months with lifestyle intervention and metformin monotherapy or dual therapy, respectively (unless contraindications to metformin exist). Preference is not given for which agent(s) should be added to metformin (drug choice should be individualized based on patient characteristics). If HbA1c target not achieved after ~3 months of triple therapy, consider initiating basal insulin (usually with metformin +/- other noninsulin agent) or if patient already receiving an optimally titrated basal insulin (ie, a long-acting insulin such as glargine, degludec, or detemir) as part of their regimen, consider combination injectable therapy (ADA 2017f).

Combination injectable therapy: If HbA1c target has not been met with basal insulin (ie, long-acting insulin such as glargine, degludec or detemir) (usually combined with metformin +/- other noninsulin agent), despite titrating basal insulin to provide acceptable fasting blood glucose concentrations, combination injectable therapy should be considered. Options include: adding a rapid-acting insulin (eg, lispro, aspart, glulisine) prior to largest meal or adding a GLP-1 receptor agonist or changing from basal insulin to a twice daily premixed insulin. If HbA1c still not adequately controlled, consider advancing from one rapid-acting insulin prior to largest meal to ‘basal-bolus’ regimen (ie, rapid-acting insulin administered before ≥2 meals) or consider advancing from a twice daily premixed insulin to a 3 times daily premixed insulin (ADA 2017f).

Patients with elevated HbA1C at therapy initiation: If HbA1c is ≥9% at initiation of therapy, dual therapy (metformin + a second antihyperglycemic agent) should be considered. If HbA1c ≥10%, blood glucose is ≥300 mg/dL or if patient is symptomatic (eg, polyuria, polydipsia), insulin therapy (with or without additional agents) should be considered (ADA 2017f).

Hyperglycemia, critically ill (off-label use): 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). 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).

Diabetic ketoacidosis, mild to moderate (off-label use): Subcutaneous injection:

1-hour interval dosing: Initial: 0.3 units/kg, followed by 0.1 units/kg every hour until blood glucose <250 mg/dL, then decrease to 0.05 units/kg every hour until resolution of ketoacidosis (Umpierrez 2004).

2-hour interval dosing: Initial: 0.3 units/kg, followed by 0.2 units/kg 1 hour later and then every 2 hours thereafter until blood glucose <250 mg/dL, then decrease to 0.1 units/kg every 2 hours until resolution of ketoacidosis (Umpierrez 2004).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Insulin aspart is a rapid-acting insulin analog which is normally administered SubQ as a premeal component of the insulin regimen or as a continuous SubQ infusion and should be used with intermediate- or long-acting insulin. When compared to insulin regular, insulin aspart has a more rapid onset and shorter duration of activity. In carefully controlled clinical settings with close medical supervision and monitoring of blood glucose and potassium, insulin aspart may also be administered IV in some situations. Insulin requirements vary dramatically between patients and dictate frequent monitoring and close medical supervision. Fiasp is not approved for use in pediatric patients (has not been studied).

General insulin dosing (off-label):

Diabetes mellitus, type 1: Children and Adolescents: 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: SubQ: 0.2 to 0.6 units/kg/day in divided doses. Conservative initial doses of 0.2-0.4 units/kg/day are often recommended to avoid the potential for hypoglycemia. A rapidly acting insulin may be the only insulin formulation used initially.

Usual maintenance range: SubQ: 0.5 to 1 unit/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)

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 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): 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.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustments may be needed. Renal impairment may change insulin requirements; monitor blood glucose closely.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; however, dosage adjustments may be needed. Hepatic impairment may change insulin requirements; monitor blood glucose closely.

Dosing: Obesity

Refer to indication-specific dosing for obesity-related information (may not be available for all indications).

Reconstitution

For SubQ administration:

Fiasp: Do not dilute or mix with any other insulin products or solutions.

NovoLog: Vials may be diluted with Insulin Diluting Medium for NovoLog to a concentration of 10 units/mL (U-10) or 50 units/mL (U-50). Do not dilute insulin contained in a cartridge, prefilled pen, or if using in an external insulin pump.

For IV infusion: May be diluted in compatible fluid (eg, NS) to 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. Cold injections should be avoided. SubQ administration is usually made into the thighs, arms, or abdomen; Novolog may also be administered in the buttocks. Rotate injection sites within the same region to avoid lipodystrophy.

Fiasp: Inject at the beginning of or within 20 minutes after starting a meal. Do not mix with any other insulin products or solutions.

Novolog: Administer immediately (within 5 to 10 minutes) before a meal. Novolog from a vial may be mixed with insulin NPH only (do not mix with other types of insulin) but should be drawn into syringe first. Do not dilute or mix other insulin formulations with Novolog contained in a cartridge or prefilled pen.

CSII administration (Novolog): Do not use if solution is viscous or cloudy; use only if clear and colorless. Patients should be trained in the proper use of their external insulin pump and in intensive insulin therapy. Infusion sets and infusion set insertion sites should be changed at least every 3 days; rotate infusion sites. Insulin in reservoir should be changed at least every 6 days. Do not dilute or mix other insulin formulations with insulin aspart that is to be used in an external insulin pump.

IV administration: 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. Do not administer insulin mixtures intravenously.

IV infusions: To minimize insulin adsorption to plastic IV tubing: Although data is lacking regarding adsorption with insulin aspart, insulin regular loss has been shown to 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.

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

Unopened vials, cartridges, and prefilled pens may be stored under refrigeration between 2°C and 8°C (36°F to 46°F) until the expiration date or at room temperature <30°C (<86°F) for 28 days; do not freeze; keep away from heat and sunlight. Once punctured (in use), Novolog or Fiasp vials may be stored under refrigeration or at room temperature <30°C (<86°F); use within 28 days. Novolog cartridges and prefilled pens that have been punctured (in use) should be stored at temperatures <30°C (<86°F) and used within 28 days; do not freeze or refrigerate. Opened (in use) Fiasp flex touch pens may be stored at room temperatures <30°C (<86°F) or under refrigeration at 2°C and 8°C (36°F to 46°F) and should be used within 28 days.

When used for CSII (Novolog): Insulin aspart contained within an external insulin pump reservoir should be replaced at least every 6 days; discard if exposed to temperatures >37°C (>98.6°F).

Dilution for SubQ administration (Novolog vials): Diluted insulin aspart should be stored at temperatures <30°C (<86°F) and used within 28 days.

For IV infusion: Stable in compatible fluid (eg, NS) for 24 hours at room temperature.

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

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

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

Rates of adverse reactions were defined during combination therapy with NPH insulin.

>10%:

Endocrine & metabolic: Hypoglycemia (Type 1 combination regimens: 75%; Type 2 combination regimens: 27%), severe hypoglycemia (Type 1 combination regimens: adults administration: 17%, children & adolescents administration: 6%; Type 1 combination regimens: children & adolescents insulin pump administration: 10%; adults insulin pump administration: 2%; Type 2 combination regimens: 10%)

Central nervous system: Headache (5% to 12%), hyporeflexia (11%)

Miscellaneous: Accidental injury (11%)

1% to 10%:

Cardiovascular: Chest pain (5%)

Central nervous system: Sensory disturbance (9%)

Dermatologic: Onychomycosis (10%), skin changes (5%)

Gastrointestinal: Nausea (7%), abdominal pain (5%), diarrhea (5%)

Genitourinary: Urinary tract infection (8%)

Respiratory: Sinusitis (5%)

>1% (Limited to important or life-threatening): Anaphylaxis, local hypersensitivity reaction (secondary to excipient metacresol), myalgia (secondary to excipient metacresol)

Warnings/Precautions

Concerns related to adverse effects:

• Hypersensitivity: Hypersensitivity reactions (serious, life-threatening and anaphylaxis) have occurred. If hypersensitivity reactions occur, discontinue administration and initiate supportive care measures.

• Hypoglycemia: The most common adverse effect of insulin is hypoglycemia. The timing of hypoglycemia differs among various insulin formulations. Hypoglycemia may result from increased work or exercise without eating; use of long-acting insulin preparations (eg, insulin degludec, insulin detemir, insulin glargine) may delay recovery from 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 use and supplement potassium when necessary.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment. Risk of hypoglycemia may be increased; more frequent monitoring and dosage adjustments may be required.

• Renal impairment: Use with caution in patients with renal impairment. Risk of hypoglycemia may be increased; more frequent monitoring and dosage adjustments may be required.

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 (insulin regular) in the inpatient hospital setting is strongly discouraged. In the critical care setting, continuous IV insulin infusion (insulin regular) 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 2017d).

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).

Other warnings/precautions:

• Appropriate use: Due to the short duration of action of insulin aspart, a longer acting insulin or CSII via an external insulin pump is needed to maintain adequate glucose control in patients with type 1 diabetes mellitus (insulin dependent, IDDM). In both type 1 and type 2 diabetes, preprandial administration of insulin aspart should be immediately followed by a meal within 5 to 10 minutes.

• Continuous subcutaneous insulin infusion (CSII) administration: NovoLog may be administered via CSII; do not dilute or mix with other insulin formulations. Rule out external pump failure if unexplained hyperglycemia or ketosis occurs; temporary SubQ insulin administration may be required until the problem is identified and corrected.

• IV administration: Insulin aspart may be administered IV in selected clinical situations to control hyperglycemia; close monitoring of blood glucose and serum potassium as well as medical supervision is required.

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

Monitoring Parameters

Critically-ill patients receiving insulin aspart 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 2017a]); renal function; hepatic function, weight

IV administration: Close monitoring of blood glucose and serum potassium

Pregnancy Risk Factor

B (product dependent)

Pregnancy Considerations

Dose-related adverse effects were observed in animal reproduction studies. Insulin aspart can be detected in cord blood (Pettitt 2007).

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 2017c; 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 2017c; Blumer 2013; Kitzmiller 2008; Lambert 2013).

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 (ADA 2017c). 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). Insulin aspart may be used to treat diabetes in pregnant women (ACOG 2013; Blumer 2013; Kitzmiller 2008; Lambert 2013).

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?)

• 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), shortness of breath, excessive weight gain, swelling of arms or legs, burning or numbness feeling, vision changes, chills, severe dizziness, passing out, mood changes, seizures, slurred speech, severe injection site irritation, 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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