NOVOLOG (Brand for INSULIN ASPART)

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

Route-Specific Administration

Injectable Administration
-Insulin aspart is administered by subcutaneous or intravenous injection. Do NOT administer by intramuscular injection.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Do not use injections that are unusually viscous, cloudy, or discolored.
-Patients using insulin vials should never share needles or syringes with another person.

Insulin Pens:
-Insulin aspart is available in one concentration as a prefilled pen: 100 units/mL. Ensure proper product selection. NovoLog and Fiasp are NOT interchangeable, due to different directions for timing of subcutaneous dosing.
-Insulin pens should never be shared among patients. Even if the disposable needle is changed, sharing may result in transmission of hepatitis viruses, HIV, or other blood-borne pathogens. Do not share pens among multiple patients in an inpatient setting; use multidose vials instead, if available, or, reserve the use of any pen to 1 patient only.
-Ensure that the patient knows how to use the type of pen needles being dispensed.-For standard pen needles with both an outer cover and an inner needle cover, remove both covers before use.
-For the safety pen needle, remove only the outer cover; the fixed inner needle shield remains in place.

-Insulin should never be withdrawn from an insulin pen cartridge.
Intravenous Administration
Continuous IV Infusion
Novolog:
-Insulin aspart can be diluted with 0.9% Sodium Chloride Injection to a concentration of 0.05 to 1 units/mL in polypropylene infusion bags.
-Close monitoring of blood glucose and potassium concentrations are required to avoid hypoglycemia and hypokalemia.
-Storage: Infusion bags are stable at room temperature for 24 hours. A certain amount of insulin will initially be adsorbed to the infusion bag.

Fiasp:
-Insulin aspart can be diluted with 0.9% Sodium Chloride Injection or 5% Dextrose Injection to a concentration of 0.5 to 1 units/mL in polypropylene infusion bags.
-Close monitoring of blood glucose and potassium concentrations are required to avoid hypoglycemia and hypokalemia.
-Storage: Infusion bags are stable at room temperature for 24 hours. A certain amount of insulin will initially be adsorbed to the infusion bag.

Subcutaneous Administration
Intermittent Subcutaneous Injection
-Preferably, administer Novolog insulin aspart immediately before a meal (i.e., meal starts within 5 to 10 minutes after injection) and Fiasp insulin aspart at the start of a meal or within 20 minutes after starting a meal. In exceptional cases (e.g., toddlers who are reluctant eaters), insulin aspart can be given immediately after eating.
-Insulin aspart is available in a multi-dose vial and 3 mL cartridges for use in various insulin pen devices (see specific product labeling). In an effort to minimize insulin wastage, some experts suggest the use of the 3 mL cartridges for children on small doses of insulin. However, once any insulin has been withdrawn from a cartridge using a syringe, that cartridge should not be used in an insulin pen device because the inadvertent introduction of air into the cartridge can alter the pen's mechanics resulting in inaccurate dosing.
Administration
-Subcutaneous injections are usually made into the anterior and lateral aspects of the thigh, the upper arms, buttocks, or the abdomen
-Rotate injection sites within the same region with each injection to prevent lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring.

Insulin Aspart Pens:
-Novolog Flexpen:
--The needle should remain in the skin for at least 6 seconds to ensure complete delivery of the insulin dose (the patient should slowly count to 6).
-Dials doses in 1 unit increments and delivers a maximum dose of 60 units per injection.
-Storage of Novolog FlexPen and cartridges: Once punctured or in use, store at room temperature below 30 degrees C (86 degrees F) for up to 28 days; do NOT refrigerate. Do not expose to excessive heat or direct light.

-Fiasp FlexTouch
--The needle should remain in the skin for at least 6 seconds to ensure complete delivery of the insulin dose (the patient should slowly count to 6).
-Dials doses in 1 unit increments and delivers a maximum dose of 80 units per injection.
-Storage of FlexTouch pens: Once in use, store at temperatures below 30 degrees C (86 degrees F) for up to 28 days. Do not expose to excessive heat or direct light. May refrigerate.
-Storage of PenFill cartridges: Once in use, store at room temperature (i.e., less than 30 degrees C or 86 degrees F) for up to 28 days; do NOT refrigerate. Do not expose to excessive heat or direct light.


Insulin Aspart Vials:
-Storage of Opened Novolog Vials: Store at temperatures below 30 degrees C (86 degrees F) for up to 28 days. Do not expose to excessive heat or direct light. May refrigerate.
-Storage of Opened Fiasp Vials: Store at temperatures below 30 degrees C (86 degrees F) for up to 28 days. Do not expose to excessive heat or direct light. May refrigerate.
Dilution
-Fiasp insulin aspart should not be diluted or mixed with any other insulin products.
-Novolog insulin aspart may be diluted to a concentration of 10 units/mL or 50 units/mL using Insulin Diluting Medium for Novolog.
-Storage: Novolog insulin aspart diluted to 10 units/mL or 50 units/mL using Insulin Diluting Medium for Novolog can be stored at temperatures below 30 degrees C (86 degrees F) for up to 28 days.
Mixing of Insulin Aspart for Intermittent subcutaneous Injection
-According to the FDA-approved product labeling, Novolog insulin aspart may be mixed with NPH human insulin only.
-When mixing insulin aspart and NPH human insulin together in a syringe, draw insulin aspart into the syringe first to prevent contamination of the remaining insulin aspart in the vial by the NPH insulin.
-The product labeling for insulin glargine (Lantus) states that it should not be diluted or mixed with any other insulin; however, limited data suggest that mixing insulin glargine with insulin aspart does not affect glycemic control or rates of hypoglycemia in children with Type 1 diabetes mellitus (DM). In these studies, the insulins were mixed immediately before injection. Cloudiness upon mixing was noted, but neither pain upon injection nor clogging of the needle was reported.

Continuous Subcutaneous Insulin Infusion (CSII)
Preparation and Pump Selection
-Do not mix insulin aspart with other insulins or diluents when using in an external pump.
-Follow recommendations available from the manufacturers of insulin aspart and the specific insulin pump to be used.
-Insulin aspart is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Check the recommended reservoir and infusion sets in the pump manual.
Administration via CSII pump
-Novolog
--Pre-meal boluses should be infused immediately (within 5 to 10 minutes) before meals.
-Rotate the infusion site within the same general region according to the manufacturer's user manual. A new injection site should be selected if a current site becomes erythematous, pruritic, or thickened as skin reactions or alterations in absorption can occur. Such changes in the skin surrounding an infusion site should be reported to a healthcare provider.
-For insulin pump use, the total in-use time for insulin aspart vials is 19 days, including 7 days pump in-use time.
-Change the insulin aspart in the reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Do not expose to temperatures exceeding 37 degrees C (98.6 degrees F). Change the infusion sets according to the manufacturer's user manual. When insulin aspart is maintained in a pump system for longer than recommended or at high temperatures, pump malfunction, loss of m-cresol, and insulin degradation may occur.

-Fiasp
--Pre-meal boluses should be infused immediately at the start meal or within 20 minutes after starting a meal.
-Administer Fiasp insulin aspart by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis.
-Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure.
-A new injection site should be selected if a current site becomes erythematous, pruritic, or thickened as skin reactions or alterations in absorption can occur. Such changes in the skin surrounding an infusion site should be reported to a healthcare provider.
-For insulin pump use, the total in-use time for insulin aspart vials is 28 days, including 6 days pump in-use time
-Change insulin aspart in the pump reservoir at least every 6 days, or according to the pump user manual, whichever is shorter. Follow the Fiasp-specific information for in-use time because Fiasp-specific information may differ from general insulin pump user manual instructions. Change the infusion set and the infusion set insertion site according to the manufacturer's user manual. Do not expose Fiasp insulin aspart in the pump reservoir to temperatures greater than 37 degrees C (98.6 degrees F).

Hypoglycemia is the most common adverse reaction to insulin therapy; educate patients and caregivers about the prevention and management of hypoglycemia. Severe hypoglycemia was reported in 1.1% of pediatric patients receiving mealtime insulin aspart (Fiasp) plus insulin degludec and 3.1% of pediatric patients receiving in postmeal insulin aspart (Fiasp) plus insulin degludec. Pediatric patients with Type 1 diabetes treated with mealtime and postmeal insulin aspart (Fiasp) reported a higher rate of blood glucose confirmed hypoglycemic episodes compared to patients treated with Novolog insulin aspart; the imbalance was greater during the nocturnal period. Because individual patients have different thresholds, there is no single numerical definition for hypoglycemia; however, in clinical practice, a blood glucose of less than 70 mg/dL is a common threshold for treatment in pediatric patients. Patients experiencing symptoms of hypoglycemia should be immediately given simple carbohydrate to raise blood glucose. Mild events can be treated with 10 to 15 grams oral glucose; severe episodes can be treated with IV dextrose (2 to 3 mL/kg dextrose 10%) or IM or subcutaneous glucagon (0.5 to 1 mg depending on age/weight). Also, patients should ingest a full snack or meal shortly after that to prevent recurrence of hypoglycemia. Infants and young children are at greater risk for hypoglycemia; they often have unpredictable appetites and activity levels, which complicate the prediction of insulin requirements. Also, young children are often unaware of hypoglycemia symptoms, which may delay proper treatment. Physical activity also increases the risk of hypoglycemia during and immediately after exercise and again approximately 7 to 12 hours after exercise. A source of simple carbohydrate should be readily available before, during, and after exercise. Targeting aggressive blood glucose and A1C goals may also increase the risk of hypoglycemia. Less stringent A1C goals (e.g., A1C less than 8.5%) may be appropriate for patients with a history of severe hypoglycemia or hypoglycemia unawareness. Individualize blood glucose and A1C targets with the goal of achieving the best possible control while minimizing the risk of hypoglycemia and maintaining normal growth and development. The incidence of hypoglycemia is difficult to estimate because definitions of hypoglycemia in clinical trials vary. The rate of severe hypoglycemia is thought to be 5 to 20 per 100 patient-years in children. While this rate has declined over the last decade, it is still higher than that of adults. Signs and symptoms of hypoglycemia can include hunger, pallor, nauseousness or vomiting, fatigue, sweating, head pain, palpitations, numbness of the mouth, tingling in the fingers, tremor, muscle weakness, blurred vision, confusion, tachycardia, and shallow breathing. In young children, behavioral symptoms such as irritability, sudden mood changes, crying for an unknown reason, and clumsiness may be the main presenting symptoms. In severe cases, seizures and loss of consciousness can occur and require emergency treatment. Prolonged hypoglycemia can result in irreversible brain damage and even death. Using insulin analogs rather than traditional human insulin may carry a lower risk of hypoglycemia in some patients; insulin analogs, both rapid-acting (insulin aspart, insulin glulisine, and insulin lispro) and basal insulin analogs (insulin detemir and insulin glargine), have been associated with a decreased incidence of hypoglycemia in clinical trials.

Insulin therapy facilitates the intracellular uptake of potassium; therefore, hypokalemia can occur. If left untreated, hypokalemia may cause respiratory paralysis, ventricular arrhythmias, and even death. Continuous intravenous infusions of insulin aspart (e.g., during the treatment of DKA) are highest risk for causing hypokalemia; monitor serum potassium concentrations frequently and replace potassium as appropriate. Hypokalemia risk is also increased in patients using potassium-lowering medications and in patients taking medications sensitive to serum potassium concentrations.

Insulin therapy, including treatment with insulin aspart, has been associated with weight gain; this has been attributed to the anabolic effects of insulin and the decrease of glucosuria.

As with any insulin product, long-term use of insulin aspart can cause lipodystrophy at the site of repeated insulin injections or infusions. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue); either of these effects can affect insulin absorption. Lipodystrophy was reported in 2.1% of pediatric patients treated with insulin aspart (Fiasp). During postmarketing use, cases of localized cutaneous amyloidosis at the injection site have been reported. In addition, hyperglycemia has been noted with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site. Rotate injection sites within the same region with each injection to prevent lipodystrophy reactions and localized cutaneous amyloidosis.

Although uncommon, localized injection site reaction, including erythema, swelling, and pruritus, has been reported with insulin aspart use. An injection site reaction was reported in 4.2% of pediatric patients treated with intermittent injections of insulin aspart (Fiasp). These reactions usually resolve in a few days to a few weeks, but in rare occasions, may require discontinuation of insulin aspart. If an injection site reaction occurs, ensure proper injection technique and if a skin cleansing agent is being used, consider using an alternate cleansing method; in some instances, the localized reaction may be due to improper injection technique or a reaction to the cleansing agent. Some experts no longer recommend disinfecting the injection site with alcohol unless hygiene is a problem. Localized reactions and generalized myalgia have been reported with injected metacresol, which is an excipient in insulin aspart. Infusion-related reactions may occur with continuous subcutaneous insulin infusion (CSII). In adult patients receiving insulin aspart (Fiasp) via CSII, 10.2% developed an infusion-related reaction.

Generalized urticaria and anaphylactoid reactions can rarely occur with insulin therapy and have been reported in postmarketing surveillance with insulin aspart. Allergic reactions were reported in 4% of pediatric patients treated with insulin aspart (Fiasp). Desensitization procedures may be necessary in some patients. Additionally, generalized allergy to insulin may also cause rash, dyspnea, wheezing, hypotension, sinus tachycardia, and/or diaphoresis.

Insulin resistance can develop in patients requiring daily insulin injections. Insulin resistance can be acute resulting from infections, surgical trauma, emotional disturbances, or other endocrine disorders. Insulin resistance can also be chronic; for patients with type 2 diabetes mellitus (DM), insulin resistance is usually associated with obesity and related to decreased tissue sensitivity to insulin. For patients with type 1 DM, chronic insulin resistance is often due to increased levels of circulating anti-insulin antibodies (AIA). All exogenously administered insulins have the ability to cause AIA. In a 26-week study in pediatric patients with Type 1 DM, among the 519 patients who received insulin aspart (Fiasp), 97.1% were positive for cross-reacting AIA at least once during the study, including 94.6% that were positive at baseline. A total of 19.1% of patients who received insulin aspart (Fiasp) were positive for anti-drug antibodies (ADA) at least once during the study, including 16% that were positive at baseline. In a 6-month study with a 6 month extension in adults with type 1 diabetes, 99.8% of patients who received insulin aspart were positive for AIA at least once during the study, including 97.2% that were positive at baseline. A total of 92.1% of patients who received insulin aspart were positive for ADA at least once during the study, including 64.6% that were positive at baseline. In another study of patients with type 1 diabetes receiving insulin aspart, initial increase in titers of antibodies to insulin, followed by a decrease to baseline values, was observed in regular human insulin and insulin aspart treatment groups with similar incidences. Antibody formation did not cause deterioration in glycemic control or necessitate increases in insulin dose. The clinical significance of antibody formation to various insulin products is not always clear, as unpredictable changes in the pharmacokinetics and pharmacodynamics of exogenous insulin are possible in the presence of AIA; however, in general, a correlation between the presence of AIA with insulin dose, A1C, or adverse reactions has not been demonstrated.

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

In a clinical trial, headache was reported in 6.1% to 10.1% of pediatric patients receiving insulin aspart (Fiasp) combined with insulin degludec. During a clinical trial comparing insulin aspart combined with NPH insulin to regular insulin combined with NPH in patients with type 1 diabetes mellitus, headache (12% and 10%, respectively) and accidental injury (11% and 10%, respectively) were reported. In patients with type 2 diabetes mellitus, hyporeflexia (11% and 7%, respectively), sensory disturbance (9% and 7%, respectively), and headache (5% and 3%, respectively) were reported.

Intensification or rapid improvement in glucose control with insulin such as insulin aspart has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

In a clinical trial, vomiting was reported in 3.4% to 8.1% of pediatric patients receiving insulin aspart (Fiasp) combined with insulin degludec. In clinical evaluation of insulin aspart combined with NPH insulin compared to regular insulin combined with NPH in patients with type 1 diabetes mellitus, gastrointestinal adverse reactions included: nausea (7% and 5%, respectively) and diarrhea (5% and 3%, respectively); in adults with type 2 diabetes, abdominal pain was reported in 5% of patients who received the insulin aspart regimen and 1% of those who received the regular insulin regimen.

Infection at the site of insulin injection is rare. Some experts no longer recommend disinfecting the skin prior to administration unless hygiene is a concern. In a clinical trial of insulin aspart (Fiasp) combined with insulin degludec in pediatric patients with Type 1 diabetes mellitus (DM), the following adverse reactions were reported: viral upper respiratory tract infection (20.5% to 23%), upper respiratory tract infection (8.4% to 12.4%), influenza (5.8% to 7.7%), rhinitis (3.8% to 6.2%), and fever (pyrexia) (6.2% to 8.4%). In clinical evaluation of insulin aspart combined with NPH insulin compared to regular insulin combined with NPH in adults with type 2 DM, adverse reactions included: onychomycosis (10% and 5%, respectively), urinary tract infection (8% and 7%, respectively), unspecified skin disorder (5% and 2%, respectively), and sinusitis (5% and 1%, respectively).

In clinical evaluation, adults with type 2 diabetes mellitus received either insulin aspart combined with NPH insulin (n = 91) or regular insulin combined with NPH (n = 91). Chest pain (unspecified) was reported in 5% of those who received the insulin aspart regimen compared to 3% of those who received the regular insulin regimen.

Insulin aspart is contraindicated for use in patients hypersensitive to the insulin or the excipients in the formulations. Minor, local sensitivity characterized by redness, swelling, or itching at the site of injection does not usually contraindicate therapy. These local reactions usually resolve in a few days, but in some cases, may require discontinuation. Insulin aspart contains m-cresol and should be avoided in patients with m-cresol hypersensitivity; localized reactions and general myalgias have been reported with the use of cresol as an injectable excipient. Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash, pruritus, shortness of breath, wheezing, hypotension, tachycardia, and diaphoresis. Severe cases, including anaphylactoid reactions, may be life threatening.

Insulin aspart is contraindicated in patients during episodes of hypoglycemia. Educate patients and caregivers on the signs and symptoms of hypoglycemia, risk factors, and management strategies. Infants and young children are at particular risk for hypoglycemia; they often have unpredictable appetites and activity levels, which complicate prediction of insulin requirements. In addition, young children are often unaware of hypoglycemia symptoms, which may delay proper treatment. Individualize blood glucose and A1C targets with the goal of achieving the best possible control while minimizing the risk of hypoglycemia and maintaining normal growth and development. Physical activity increases the risk of hypoglycemia during and immediately after exercise and again approximately 7 to 12 hours after exercise. A source of simple carbohydrate should be readily available before, during, and after exercise. Targeting aggressive blood glucose and A1C goals may also increase the risk of hypoglycemia. Less stringent A1C goals (e.g., less than 8.5%) may be appropriate for patients with a history of severe hypoglycemia and hypoglycemia unawareness. Changes in insulin, manufacturer, type, or method or site of administration may also affect glycemic control. It is essential that clinicians and patients ensure the correct insulin is dispensed and administered; this includes the correct insulin brand and concentration. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient's insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia.

A "sick-day" plan must be available for patients with diabetes to minimize the risk of DKA. Illnesses such as fever, infection, diarrhea, and vomiting can cause metabolic disturbances that alter insulin requirements; a "sick-day"' plan should instruct patients and caregivers how to take appropriate action with blood glucose monitoring and insulin therapy when acute illness is present. In addition to physical illness, thyroid disease, recent trauma or surgery, stress, emotional disturbances, and certain medications can affect insulin aspart requirements, requiring dosage adjustments.

Use insulin aspart carefully in patients who are predisposed to hypokalemia; insulin facilitates the intracellular uptake of potassium and can cause low serum potassium. Monitor patients at risk for hypokalemia (e.g., patients who are using potassium-lowering drugs or taking potassium concentration sensitive drugs) closely for these effects. Hypokalemia is a particular risk when insulin is given by continuous intravenous administration; monitor patients carefully.

Patients and caregivers of those receiving insulin aspart via continuous subcutaneous insulin infusion (CSII) administration should be fully educated on the proper use and maintenance of the pump. Advise patients that self-monitoring of blood glucose is especially important when using CSII. Pump or infusion set malfunction or insulin degradation can lead to hyperglycemia and DKA or HHS in a short time because of the small subcutaneous depot of insulin. This is especially important for rapid-acting insulin analogs that are more quickly absorbed through skin and have a shorter duration of action (e.g., insulin aspart, insulin glulisine, and insulin lispro). These differences may be particularly relevant when patients are switched from multiple injection therapy or infusion with buffered regular insulin. All patients on CSII must have an alternate insulin therapy available in case of pump failure. If hyperglycemia during CSII occurs, prompt identification of the cause of hyperglycemia is necessary.

The effect of hepatic disease, renal impairment, or renal failure on insulin aspart dosage requirements is not clear; monitor blood glucose concentrations carefully in patients with changing renal or hepatic function. Some pharmacokinetic studies have shown increased circulating concentrations of insulin in patients with hepatic or renal failure; however, other data suggest no changes in insulin aspart's pharmacokinetics in these patients.

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

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

Description: Insulin aspart is a rapid-acting insulin analog that is produced from a chemical modification of regular human insulin; the amino acid proline at position B28 in human insulin is replaced by aspartic acid. It is considered equipotent to regular insulin; however, it has a quicker onset of action, reaches maximum concentration faster, has less absorption variation, and has a shorter duration of action. Insulin aspart is often used as prandial or snack boluses in combination with longer-acting insulins or in external insulin pumps in children and adults with Type 1 diabetes mellitus (DM). The use of continuous subcutaneous insulin infusion (CSII) for up to 4 years has been reported in very young children with Type 1 DM (65 children with mean age of 4.5 years, range 1.7 to 6.9 years); the use of CSII in this population resulted in a reduction in A1C (from 7.4% to 7% at 12 months) and in the incidence of severe hypoglycemia (from 78 episodes per 100 patient years to 37 episodes per 100 patient years, a 53% reduction). Insulin aspart is also a treatment option for patients with Type 2 DM who have failed to achieve or maintain glycemic goals on oral medication. Two formulations of insulin aspart are available and are FDA-approved in pediatric patients as young as 2 years of age. Faster-acting insulin aspart (Fiasp) differs from Novolog due to its onset of action after subcutaneous administration; the product has different instructions for timing of administration with respect to meals.

General dosing information:
-Insulin aspart is a rapid-acting insulin analog equipotent to regular insulin, but with more rapid activity and a shorter duration of action when given via intermittent subcutaneous injection.
-Because of insulin aspart's short duration of action, intermittent injections should not be used as monotherapy; a longer acting insulin, a basal insulin infusion, or oral agents (type 2 diabetes only) should also be used.
-Novolog and Fiasp are not interchangeable. Novolog is given 5 to 10 minutes before a meal; Fiasp is given at the start of a meal or within 20 minutes afterward.

For the treatment of type 1 diabetes mellitus:
Subcutaneous dosage (Novolog):
Children and Adolescents 2 to 17 years: 55% to 70% of the total daily insulin dose subcutaneously divided 5 to 10 minutes before meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Subcutaneous dosage (Fiasp):
Children and Adolescents 2 to 17 years: 55% to 70% of the total daily insulin dose subcutaneously divided at the start of or within 20 minutes after starting meals, initially. Adjust dose based on metabolic needs, blood glucose, and glycemic control goal. Use intermediate or long-acting basal insulin to satisfy the remainder of the daily insulin requirements. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Continuous Subcutaneous Infusion dosage (Novolog):
Children 2 to 6 years: 30% to 35% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 5 to 10 minutes before meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Children and Adolescents 7 to 17 years: 50% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose 5 to 10 minutes before meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Continuous Subcutaneous Infusion dosage (Fiasp):
Children 2 to 6 years: 30% to 35% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose at the start of or within 20 minutes after starting meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.
Children and Adolescents 7 to 17 years: 50% of the total daily insulin dose by continuous subcutaneous infusion by insulin pump. Bolus mealtime and correction insulin dose by pump based on insulin-to-carbohydrate ratio and/or insulin sensitivity factor and target glucose at the start of or within 20 minutes after starting meals. Adjust basal dose based on overnight, fasting, or daytime glucose outside of activity of bolus doses. The typical starting total daily insulin dose is 0.25 to 0.5 unit/kg/day for prepubertal or postpubertal children and 0.5 to 0.75 unit/kg/day during puberty. The typical maintenance total daily insulin dose is often less than 0.5 unit/kg/day during the partial remission phase, 0.7 to 1 unit/kg/day for prepubertal children outside the partial remission phase, and 1 to 2 units/kg/day during puberty.

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

For the treatment of diabetic ketoacidosis*:
Subcutaneous dosage:
Children and Adolescents: 0.15 units/kg/dose subcutaneously every 2 hours beginning at least 1 hour after the start of fluid replacement therapy. May reduce dose to 0.1 units/kg/dose subcutaneously every 2 hours if blood glucose continues to decrease by more than 90 mg/dL despite the addition of dextrose to intravenous fluids. Transition to a multi-dose, basal-bolus subcutaneous insulin regimen once the acidosis is corrected and oral intake is tolerated. Subcutaneous administration of rapid-acting insulin may be considered when intravenous insulin infusion is not possible and in uncomplicated mild to moderate diabetic ketoacidosis.

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

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

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

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

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

Patients with Hepatic Impairment Dosing
Some studies have noted increased circulating levels of insulin in patients with hepatic failure. Specific dosage adjustment recommendations are not available; carefully monitor blood glucose concentrations and adjust insulin dosage as needed.

Patients with Renal Impairment Dosing
Some studies have noted increased circulating levels of insulin in patients with renal failure; insulin requirements may be reduced. Specific dosage adjustment recommendations are not available; carefully monitor blood glucose concentrations and adjust insulin dosage as needed.

*non-FDA-approved indication

Monograph content under development

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

Diabetes mellitus type 1 is caused by insulin deficiency while diabetes mellitus type 2 is caused by a combination of insulin deficiency and resistance. Biosynthetic insulin and insulin analogs are used to regulate glucose metabolism in patients with diabetes mellitus. Insulin administration also enables these patients to replete their liver glycogen stores and to convert glycogen to fat. Insulin aspart is prepared using recombinant DNA technology (utilizing S. cerevisiae yeast [baker's yeast]). Insulin aspart differs from human insulin in that the amino acid proline is replaced with aspartic acid in position B28. After subcutaneous administration, insulin aspart has a faster onset of action compared to regular insulin.

Pharmacokinetics: Insulin aspart is administered by intermittent subcutaneous injection and can also be administered via external subcutaneous insulin infusion pumps. Endogenous insulin distributes widely throughout the body. A small portion is inactivated by peripheral tissues, but the majority is metabolized by the liver and kidneys. Insulin is filtered and reabsorbed by the kidneys.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Limited data are available. In healthy adults, clearance of insulin aspart was similar to that of regular insulin after an IV infusion of each insulin type at 1.5 mUnits/kg/minute IV for 120 minutes. Furthermore, in patients with type 1 diabetes, the blood glucose profiles of IV infusion insulin aspart and IV infusion regular insulin are similar.

Subcutaneous Route
-Novolog: After subcutaneous administration, insulin aspart has a faster absorption time, faster onset of action, and shorter duration of action than regular insulin. Insulin aspart has an onset of action of roughly 10 to 20 minutes and a duration of approximately 3 to 5 hours. Insulin aspart reaches mean peak plasma concentrations faster (40 to 50 minutes) than regular insulin when given subcutaneously. After subcutaneous administration in healthy adults, insulin aspart had an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.
-Fiasp: In a study of adult patients with Type 1 diabetes mellitus, insulin aspart appeared in the circulation at approximately 2.5 minutes after subcutaneous administration. The onset of action was 5 minutes earlier and time to maximum glucose reduction was 11 minutes earlier with the Fiasp product than with the Novolog product. The time to maximum insulin concentrations (Tmax) was achieved approximately 63 minutes after subcutaneous administration, with peak insulin effects occurring 91 to 133 minutes after administration. The total insulin exposure and maximum insulin concentration increase proportionally with increasing subcutaneous dose of insulin aspart within the therapeutic dose range. Insulin aspart exhibits a duration of action of roughly 3 to 5 hours which is shorter than the duration of regular insulin; in general the Fiasp product has been reported to have a shorter duration of action than the Novolog product.


-Special Populations
Pediatrics
-Novolog: The pharmacokinetic and pharmacodynamic properties of insulin aspart (Novolog) and regular human insulin were evaluated in a single dose study in 18 children (6 to 12 years, n = 9) and adolescents (13 to 17 years [Tanner grade more than 2], n = 9) with type 1 diabetes mellitus (DM). The relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with type 1 DM between insulin aspart (Novolog) and regular human insulin were similar to those in healthy adult subjects and adults with type 1 DM.
-Fiasp: In children (6 to 11 years) and adolescents (12 to 18 years), the Fiasp product had an earlier onset of exposure and a higher early insulin exposure compared to Novolog. However, the total exposure and maximum concentration compared to Novolog. Onset and early insulin exposure of Fiasp was similar in children and adolescents to that in adults. Total exposure of Fiasp was lower in children and adolescents compared to adults when dosed with 0.2 units/kg body weight, while the maximum serum insulin aspart concentration was similar between age groups.

Hepatic Impairment
In a very small study of adults with either normal hepatic function (n = 6) or mild (n = 6), moderate (n = 6), or severe (n = 6) hepatic impairment, there was no correlation between degree of hepatic impairment and any pharmacokinetic parameter of insulin aspart. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver failure; therefore, careful monitoring is warranted in patients with hepatic impairment.

Renal Impairment
In a very small study of adults with either normal renal function (n = 6) or mild (n = 7), moderate (n = 3), or severe (n = 2) renal impairment, there was no apparent effect of creatinine clearance on AUC and Cmax of insulin aspart. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal failure; therefore, careful monitoring is warranted in patients with renal impairment.