Insulin Aspart

Insulin Aspart is part of the drug class:

• Insulins and analogues for injection, fast acting

Tell your doctor about all the medicines you take including prescription and non-prescription medicines, vitamins, and herbal supplements. Especially tell your doctor if you take:

• oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide antibiotics. These medicines may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia (low blood sugar).
• corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics. These medicines may reduce the blood-glucose-lowering effect.
• Beta-blockers, clonidine, lithium salts, and alcohol. These may either potentiate or weaken the blood-glucose-lowering effect of insulin.
• Pentamidine as it may cause hypoglycemia (low blood sugar), which may sometimes be followed by hyperglycemia (high blood sugar).
• beta-blockers, clonidine, guanethidine, and reserpine. These medicines may reduce the signs of hypoglycemia (low blood sugar).

Never share an injection pen, cartridge, or syringe with another person, even if the needle has been changed.

Contraindications

• Known hypersensitivity to insulin aspart or any ingredient in the formulation.1

• Hypoglycemic episodes.1

Warnings/Precautions

Warnings

More rapid onset and shorter duration of action than insulin human (regular).1 2 3 4 5 10 11 Patients with type 1 diabetes mellitus generally require a longer-acting insulin to maintain adequate glycemic control.1

Most common adverse effect of insulins.1 6 7 Monitor blood glucose concentrations.1 6 7 15

Rapid changes in serum glucose concentrations may precipitate manifestations of hypoglycemia, regardless of glucose concentrations.1 Early warning signs of hypoglycemia may differ or be less pronounced in patients with a longer duration of diabetes, diabetic neuropathy, and/or those receiving concomitant therapy with β-adrenergic blocking agents or intensive insulin therapy.1 Possible severe hypoglycemia and loss of consciousness prior to patient awareness of hypoglycemia.1

Risk of hyperglycemia and ketosis in a short time period with pump or infusion set malfunctions or insulin degradation.1

Because of rapid absorption and short duration of action, such effects may occur when patients are switched from multiple injection therapy or infusion with buffered regular insulin.1 Prompt identification and correction of hyperglycemia or ketosis is necessary.1 May require interim therapy with intermittent sub-Q injections.1

Sensitivity Reactions

Localized allergic reactions (e.g., pruritus, erythema, swelling) at injection site reported.1 15 Such reactions usually resolve within a few days to a few weeks, but occasionally may require discontinuance of insulin aspart.1 15

Generalized hypersensitivity reactions (e.g., rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, diaphoresis) reported less frequently than localized reactions, but may be life-threatening.1

Localized reactions and generalized myalgias reported with use of cresol, an excipient in the NovoLog and NovoLog Mix 70/30 formulations.1 15

Can stimulate transient formation of antibodies to insulin that may cross react with insulin aspart or insulin human.1 3 24 No consistent relationship between antibody formation and glycemic control (as measured by HbA1c) observed, and dosage adjustments not necessary to maintain glycemic control.1 24 Clinical importance unknown.1 3

General Precautions

Care should be taken in patients most at risk for development of hypoglycemia and hypokalemia, such as those who are fasting, have autonomic neuropathy, or are taking potassium-lowering drugs or drugs sensitive to serum potassium concentrations.1

Rapid onset of action of IV insulin aspart necessitates increased attention to potential hypoglycemia and hypokalemia.1 Monitor closely serum glucose and potassium concentrations during IV administration of insulin to avoid potentially fatal hypoglycemia or hypokalemia.1

To prevent medication errors, the packaging colors for Novolog have been changed to differentiate it from Novolog Mix 70/30.21 23 (See Dispensing and Administration Precautions under Dosage and Administration.)

Atrophy or hypertrophy of sub-Q fat tissue may occur at sites of frequent insulin injections; 1 6 10 injection site rotation may reduce or prevent these effects.1 6 10

Insulin requirements may be altered during illness, emotional disturbances, or stress.1

Specific Populations

Category B for insulin aspart.1 Category C for insulin aspart in fixed combination with insulin aspart protamine.15

Not known whether insulin aspart is distributed into milk.1 Use caution.1

Safety and efficacy of insulin aspart in fixed combination with insulin aspart protamine not established in children.15

The safety and efficacy of insulin aspart were comparable to that of insulin human in several clinical studies in children and adolescents 2–18 years of age with type 1 diabetes mellitus.1 8

Insufficient experience in patients ≥65 years of age to determine whether safety differs from younger adults.1 Efficacy (as measured by HbA1c) similar to that in younger adults, particularly in patients with type 2 diabetes mellitus.1 (See Geriatric Patients under Dosage and Administration.)

Common Adverse Effects

Hypoglycemia, hypersensitivity reactions, lipodystrophy, pruritus, rash, injection site reactions.1

(IN soo lin AS part)

0.2 to 0.3 hours; Peak effect: 1 to 3 hours

Time to Peak

Plasma: 40 to 50 minutes

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

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 (Dellinger 2013).

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/hour until blood glucose <250 mg/dL, then decrease to 0.05 units/kg/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).

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.

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.

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

For SubQ administration: 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 external insulin pump.

For IV infusion: May be diluted in compatible fluid (eg, NS) to concentrations of 0.05 to 1 unit/mL.

Concerns related to adverse effects:

• 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.

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

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: 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.

• 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.

Individualize dose based on metabolic needs and frequent monitoring of blood glucose
-Total daily insulin requirements are generally between 0.5 to 1 unit/kg/day; 50% to 70% of total daily requirements are generally provided by prandial insulin with the remainder provided by intermediate-acting or long-acting basal insulin
-Use HbA1c values to guide therapy; consult current guidelines for optimal target ranges

Multiple-daily injection (MDI):
-Administer subcutaneously immediately before a meal (within 5 to 10 minutes) or soon after the start of a meal
-Match prandial insulin dose to carbohydrate intake, pre-meal blood glucose, and anticipated activity
-Use in combination with an intermediate-acting or long-acting basal insulin

Continuous Subcutaneous Infusion (Insulin Pump)
-Initial programming should be based on the total daily insulin dose of previous MDI regimen; check with pump labeling to ensure the pump has been evaluated with this insulin
-While there is significant interpatient variability, approximately 50% of the total dose is provided as meal-related boluses and the remainder as a basal infusion

Intravenous Administration
-Dilute to a concentration of 0.05 to 1 unit/mL in normal saline in an infusion system using polypropylene infusion bags; closely monitor blood glucose and serum potassium during administration

Use: To improve glycemic control in adult patients with diabetes mellitus.

Successful treatment of hyperglycemic emergencies such as diabetic ketoacidosis (DKA) and hyperosmolar state (HHS) requires frequent monitoring of clinical and laboratory parameters while carefully correcting volume deficits, managing electrolytes, and normalizing blood glucose. Insulin therapy is used to slowly correct high glucose levels; consult current treatment protocols for specific guidance on fluid and electrolyte management.

Intravenous:
-IV insulin infusion is generally started 1 to 2 hours after initiating fluid replacement therapy
-Dose: 0.14 unit/kg/hour IV; alternatively, a bolus of 0.1 unit/kg followed by an infusion of 0.1 unit/kg/hr has been used
-If blood glucose has not fallen by 10% in first hour, give bolus of 0.14 units/kg while continuing insulin infusion.

DKA: When blood glucose concentration reaches 200 mg/dL, decrease the insulin infusion to 0.02 to 0.05 unit/kg/hr; dextrose should be added to the IV fluids to maintain a blood glucose between 150 and 200 mg/dL until resolution of DKA (serum bicarbonate level 15 mEq/L or greater, venous pH greater than 7.3, and a calculated anion gap in the normal range)

HHS: When blood glucose concentration reaches 300 mg/dL or less, decrease the insulin infusion to 0.02 to 0.05 unit/kg/hr; dextrose should be added to the IV fluids to maintain blood glucose between 250 and 300 mg/dL until resolution of HHS.

Subcutaneous:
-Rapid acting insulin analogs (lispro, aspart, and glulisine) have been used in studies for the treatment of uncomplicated mild to moderate DKA. The following regimens have been used:
-Initial dose of 0.2 unit/kg followed by 0.1 unit/kg every hour subcutaneously until blood glucose decreased below 250 mg/dL, then 0.05 unit/kg every hour until DKA resolved
-Initial dose of 0.3 units/kg followed by 0.2 unit/kg every 2 hours until blood glucose decreased below 250 mg/dL, then 0.1 unit/kg every 2 hours until DKA resolved

Comments:
-An endocrinologist or critical care specialist with training and expertise in the management of DKA or HHS should direct care; frequent monitoring of clinical and laboratory parameter is necessary as well as identification and correction of precipitating event.
-Starting insulin therapy before IV fluid replacement may precipitate shock, and increase the risk of hypokalemia and cerebral edema.
-To prevent rebound hyperglycemia, initiate subcutaneous insulin 15 to 30 minutes (rapid-acting) or 1 to 2 hours (regular insulin) before stopping the insulin infusion; alternatively, basal insulin may be administered in the evening and the insulin infusion stopped the next morning.

Use: Treatment of hyperglycemic emergencies.