Insulin aspart

Insulin aspart is an Anti-diabetic Agent belonging to the pharmacological class of fast-acting insulins.

Insulin aspart is approved for the treatment of diabetes mellitus. It is used to control high blood sugar levels in people with diabetes, including both type 1 and type 2 diabetes. It helps regulate blood glucose by facilitating sugar uptake into cells, supporting overall glycemic control in diabetic patients.

After being injected subcutaneously, insulin aspart is absorbed, transported to target tissues by the circulation, metabolised to control glucose, and primarily excreted by the kidneys. Rapid blood sugar management is possible because of its fast onset and short half-life.

The most common side effects are low blood sugar levels (hypoglycemia), headache, nasopharyngitis, and upper respiratory tract infection.

Insulin aspart is available in the form of injectable solutions and prefilled syringes.

The molecule is available in the United States, Canada, the United Kingdom, France, Japan, Germany and Australia.

Insulin aspart is an Anti-diabetic Agent belonging to the pharmacological class of fast-acting insulins.

The insulin receptor (IR), a heterotetrameric protein composed of two transmembrane beta units and two extracellular alpha units, binds to insulin aspart. The tyrosine kinase activity in the beta subunit of the receptor is stimulated when insulin binds to the alpha subunit of the insulin receptor. Insulin receptor substrates (IRS) proteins, Cbl, APS, Shc, and Gab 1, are just a few examples of the many intracellular substrates that the bound receptor phosphorylates and autophosphorylates. These proteins activate downstream signalling molecules, including PI3 kinase and Akt. Protein kinase C (PKC) and Glucose transporter 4 (GLUT4), both of which are essential for metabolism and catabolism, are controlled by Akt. In humans, insulin is stored as hexamers, but only insulin monomers can interact with IR. Aspartic acid is substituted for the proline residue at position B28, which decreases the propensity to form hexamers, increases the rate of absorption, has a quicker beginning of action, and has a shorter duration of action.

Insulin aspart action data duration typically occurs within approximately 15 minutes after injection.

The Data of Tmax of Insulin aspart occurs 45 to 90 minutes after subcutaneous injection.

The Cmax of Insulin aspart data was achieved within approximately 1 to 3 hours after injection.

Insulin aspart is available in the form of injectable solutions and prefilled syringes.

Injectable solution: To use the insulin aspart injectable solution, prepare the dose, identify an injection site, disinfect it, administer the insulin subcutaneously, and cautiously dispose of the needle. For proper use, adhere to the doctor's recommendations.

Prefilled pen: To use the insulin aspart prefilled pen, identify the injection site, disinfect it, attach a new needle, prepare the pen, dial the dose, inject, and cautiously dispose of the needle. For proper use, adhere to the doctor's recommendations.

The physician determines the exact dosage and timing based on the patient's needs and blood sugar levels.

• It is frequently administered to people with type 1 diabetes, a disease in which the body does not make insulin. In these people, insulin aspart helps in blood sugar regulation.
• It is used in people with type 2 diabetes who may require insulin therapy, and insulin aspart can manage their blood sugar levels effectively.
• To help people with diabetes maintain better glucose control, insulin aspart is especially beneficial in reducing the rise in blood sugar after meals.

In Treatment of diabetes mellitus

Insulin aspart is a fast-acting insulin that aids in controlling high blood glucose (sugar) levels, allowing for better post-meal blood sugar control. It provides flexibility in dosing, reducing the risk of hypoglycemia. Compatible with insulin pumps, it improves meal planning and quality of life. When used effectively, it helps achieve target A1C levels, lowering the risk of complications.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be decreased with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

• Insulin Aspart is indicated to enhance glycemic control in adults and pediatric patients with diabetes mellitus.
• It is indicated when Type 2 Diabetes Mellitus is inadequately controlled by diet, weight reduction, exercise, or oral medication.

Parenterally: Insulin aspart is available as an injection solution that can be administered parenterally. Before injection, ensure proper mixing (if required) and inspect for particles or colour changes. It is also advised to take subcutaneously within 5-10 minutes before a meal with the dose adjusted to match your carbohydrate intake. Administer insulin aspart as a subcutaneous injection under the skin, usually into the thigh, abdomen, or upper arm, using an insulin syringe, insulin pen, or insulin pump. Change the site of injection within the same region to prevent lipodystrophy. Administer SC or IV and not IM. Never combine the shots when using insulin; always give them separately. The injections of insulin and Insulin aspart may be administered in the same area of the body, but they shouldn't be close together.

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Injection solutions: 100 units/mL

Prefilled syringe: 100units/mL

Insulin aspart is available in the form of injectable solutions and prefilled syringes.

Dose Adjustment in Adult Patients:

Type 1 Diabetes Mellitus

It is possible to provide divided doses of 0.2–0.6 units/kg/day; cautious dosages of 0.2–0.4 units/kg/day are frequently advised to lower the risk of hypoglycemia.

The daily maintenance insulin needed can vary, typically from 0.5 to 1 unit/kg/day. Non-obese people may require 0.4 to 0.6 units/kg/day, while obese people may need 0.6 to 1.2 units/kg/day.

Type 2 Diabetes Mellitus

Regular insulin or fast-acting insulin (aspart insulin) before meals is also advised; however, ten units/day SC (or 0.1-0.2 units/kg/day) in the evening or split every 12 hours of an intermediate (such as NPH) or long-acting insulin is indicated.

Dosing Considerations

The balance is divided and given as fast-acting insulin, such as insulin aspart, before or at mealtimes when used in a meal-related SC injection therapy regimen. Intermediate-acting or long-acting insulin may supply 50–75% of total insulin needs.

Some individuals may need more basal insulin and total insulin to avoid premeal hyperglycemia than they would with regular human insulin because of the relatively quick start and brief duration of insulin aspart glucose-lowering effect.

Individualised dosage and blood and urine glucose monitoring are required for all patients undergoing insulin treatment.

The amount of insulin needed may fluctuate under stress, when suffering from a severe disease, or when exercising, eating, or taking medications together.

Insulin aspart should be used in treating Diabetes Mellitus, along with appropriate nutritional limits.

While taking Insulin aspart, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels. It is advised to take insulin aspart shortly before or after a meal to control blood sugar effectively.

Limit or avoid the intake of alcohol as it can interfere with blood sugar regulation.

Consume foods with a lower glycemic index to help stabilize blood sugar levels.

Be cautious about the risk of low blood sugar, particularly when combined with other diabetes medications that can cause hypoglycemia. Always carry a source of fast-acting glucose (like glucose tablets) to raise blood sugar if needed.

It is advised to stay hydrated, maintain a rich, balanced diet with appropriate carbohydrate intake, and consume plenty of vegetables, whole grains, fruits, and lean proteins to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Insulin aspart may be contraindicated in the following conditions:-

• During episodes of hypoglycemia,
• Documented hypersensitivity to Insulin Aspart or one of its excipients

• Diarrhoea, nausea/vomiting, malabsorption, hypothyroidism, renal impairment, and hepatic impairment all result in decreased insulin needs; cautiously monitor medication in these conditions.
• Fever, hyperthyroidism, trauma, infection, and surgery increase the need for insulin.
• Changes to insulin strength, manufacturer, type, or administration method may affect glycemic control and put a patient at risk for hypoglycemia or hyperglycemia; as a result, these changes should be made cautiously and only under close medical supervision. Blood glucose monitoring intervals should also be increased.
• All insulin products have the potential to move potassium from the extracellular to intracellular space, which may result in hypokalemia; untreated hypokalemia may result in respiratory paralysis, cardiac arrhythmia, and death. If necessary, check potassium levels in those at risk for hypokalemia (such as those who are using potassium-sensitive drugs or taking medicines that reduce potassium levels).
• When used with insulin, thiazolidinediones, PPAR-gamma agonists, can produce dose-related fluid retention, which may cause or aggravate heart failure. Consider stopping thiazolidinediones while monitoring for heart failure symptoms and indications.
• Patients should never share pens with others when using vials, even if the needle has been replaced. They should also never share needles or syringes with anyone else.
• Patients should read the insulin label before each injection to prevent unintentional product mix-ups.
• In the event of hypersensitive responses, stop therapy, administer primary medical care, and keep an eye on the patient until symptoms and indications are entirely off.
• Because the malfunction of an insulin pump, insulin infusion set, or insulin degradation can quickly cause hyperglycemia and ketoacidosis, patients who use continuous SC insulin infusion pump therapy must be instructed to administer insulin by injection and have alternative insulin therapy available in case of pump failure.
• Products containing insulin may result in salt retention and oedema, significantly if previously poor metabolic control is improved by enhanced insulin therapy.
• Hypoglycemia or Hyperglycemia Associated with Modifications in Insulin Regimen: Changes in an insulin regimen (such as insulin strength, manufacturer, type, injection location, or delivery technique) may impact glycemic control and increase the risk of hypoglycemia or hyperglycemia. A quick shift in the injection location (to an unaffected area) has been observed to cause hypoglycemia. In contrast, repeated insulin injections into regions of lipodystrophy or localised cutaneous amyloidosis have been documented to cause hyperglycemia. Any adjustments to a patient's insulin regimen should be made closely monitored by a doctor and with more frequent blood glucose checks. Patients who have been injected into localised cutaneous amyloidosis or lipodystrophy repeatedly should be advised to switch the injection location and be constantly watched for hypoglycemia. Modifying the dosage of concurrent anti-diabetic medications may be necessary for people with type 2 diabetes.

• Hypoglycemia, including Insulin Aspart, is the most common side effect of all insulins. Seizures, coma, and even death can result from severe hypoglycemia. Hypoglycemia can affect attention span and response speed, which might put them and others in danger when these skills are crucial. Hypoglycemia can strike unexpectedly, and each person will have different symptoms that can alter over time. Patients with long-term diabetes, those with diabetic nerve disease, those using drugs that suppress the sympathetic nervous system, such as beta-blockers, or those with recurring episodes of hypoglycemia may have less prominent symptoms of hypoglycemia.
• Hypokalemia: All insulins, including Insulin Aspart, may cause a change in potassium concentration from the extracellular to the intracellular region, which may result in hypokalemia. Hypokalemia can lead to cardiac arrhythmia, respiratory paralysis, and even death. If necessary, check potassium levels in individuals at risk for hypokalemia (such as those taking drugs that affect blood potassium concentration or those receiving treatments that reduce potassium levels.

It is unsafe to consume Insulin aspart with alcohol.

There is no sufficient scientific evidence traceable regarding the use and safety of Insulin aspart in breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.

Limit Alcohol consumption, and avoid heavy or high-fat meals.

The adverse reactions related to Insulin aspart can be categorized as:

• Common Adverse Effects: Hypoglycemia (low blood sugar), Injection site reactions (e.g., redness, swelling, itching)
• Less Common Adverse effects: Lipodystrophy, Weight gain, Peripheral oedema (swelling in extremities)
• Rare Adverse Effects: Severe allergic reactions, Insulin resistance, Skin thickening or pitting at injection site, Angioedema, Hypokalemia

Reports on Postmarketing

Hyperglycemia (with repeated injections into cutaneous amyloidosis-affected regions)

Hypoglycemia (accompanied by a rapid change to an unaffected injection site)

The clinically relevant drug interactions of Insulin aspart are briefly summarized here.

• Hypoglycemic Agents: Combining Insulin aspart with other medications that reduce blood sugar, such as sulfonylureas or other insulin products, may increase the risk of hypoglycemia. Dose adjustments may be needed.
• Beta-Blockers: Nonselective beta-blockers can mask the symptoms of hypoglycemia, making it harder for patients to recognize and treat low blood sugar levels.
• ACE Inhibitors and ARBs: These medications may enhance the hypoglycemic effect of insulin, requiring dosage adjustments.
• Other Antidiabetic Medications: Co-administration with other insulins or glucose-lowering drugs may higher the risk of hypoglycemia or hyperglycemia, necessitating dose adjustments.
• Corticosteroids: Glucocorticoids can increase blood glucose levels. Dose adjustments in Insulin aspart may be necessary when corticosteroids are initiated or discontinued.
• Oral Contraceptives: Hormonal contraceptives may affect blood sugar levels. Regular monitoring is advisable for patients using Insulin aspart and oral contraceptives.

The most common side effects of Insulin aspart include:

• Low blood glucose, or hypoglycemia
• Headache
• Nasopharyngitis, or throat and nasal passage inflammation
• Infection of the upper respiratory tract

• Pregnancy

Pregnancy Category B: Could be acceptable. Either no danger has been shown by animal research, but human studies have yet to be conducted, or some risk has been shown by animal studies but not by human studies.

There is no evidence from randomised controlled studies published during the second trimester of pregnancy linking insulin aspart to severe birth abnormalities or harmful outcomes for the mother or the foetus.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery complications. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are more likely in foetuses with poorly managed diabetes.

Human Data

There is no evidence linking insulin aspart to severe birth abnormalities or poor maternal or foetal outcomes, according to published data from 5 randomised controlled studies involving 441 pregnant women with diabetes mellitus who were given the medication in the late 2nd trimester of pregnancy. Due to methodological restrictions, such as a varying length of treatment and the bulk of the trials' small size, these studies, however, cannot conclusively prove the lack of any danger.

Animal Data

In experiments on animal reproduction, pregnant rats and rabbits were given SC insulin aspart during the organogenesis phase at exposures that were eight times and equivalent to the human subcutaneous dosage of 1 unit/kg/day, respectively. No detrimental developmental effects were seen. Higher doses led to pre-and post-implantation losses, visceral/skeletal abnormalities, and other consequences that are assumed to be related to maternal hypoglycemia; these effects are comparable to those documented in humans.

• Nursing mothers:

There is no information on the presence of insulin in breast milk, its effects on nursing infants, or how much milk is produced; however, one small published study did find that exogenous insulin, including insulin aspart, was present in breast milk; however, more research is needed to determine the effects of insulin aspart on nursing infants. Along with the mother's clinical requirement for medication, the developmental and health benefits of nursing and any potential adverse effects on the breastfed child from drugs or an underlying maternal disease should all be considered.

• Pediatric Use

In children with diabetes mellitus, the safety and efficacy of Insulin Aspart to enhance glycemic control have been established. Evidence from a sufficient and well-controlled trial of 283 paediatric patients with type 1 diabetes mellitus aged 6 to 18 years, as well as studies of adults with diabetes mellitus, support the use of Insulin Aspart.

Dose Adjustment in Pediatric Patients

Type 1 Diabetes Mellitus

During periods of growth, children may need 0.8-1.2 SC units/kg/day; adolescents may need 1.2 SC units/kg/day; otherwise, they may utilise 0.5-1 SC units/kg/day.

• Geriatric Use

In 3 controlled clinical investigations, Insulin Aspart was administered to 1,375 individuals, and 2.6% (n=36) of these patients were 65 or older. Type 1 diabetes was present in 18/1285 of these individuals, whereas type 2 diabetes was present in 18/90. In contrast to conventional human insulin, Insulin Aspart had no different effects on HbA1c according to age.

Dose Adjustment in Kidney Impairment Patients:

Patients with renal impairment may need more frequent adjustments to the dosage of Insulin Aspart and more regular blood glucose monitoring due to an increased risk of hypoglycemia.

Dose Adjustment in Hepatic Impairment Patients:

Patients with hepatic impairment may need more frequent adjustments to the dosage of Insulin Aspart and more regular blood glucose testing due to their higher risk of hypoglycemia.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to identifying and treating overdosage of Insulin aspart.

Overconsumption of Insulin aspart may lead to hypoglycemia and hypokalemia.

Management

There is no specific antidote or treatment for excessive intake of Insulin aspart. However, immediate medical attention is essential. Insulin aspart should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake.

Management typically involves supportive measures like intravenous fluids, fluid replacement to prevent dehydration, and symptomatic treatment such as antiemetic medications for nausea and vomiting.

Mild hypoglycemia can be treated with fast-acting carbohydrates or oral glucose.

Intramuscular/subcutaneous glucagon or concentrated intravenous glucose may treat more severe episodes accompanied by coma, seizure, or neurologic impairment.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

The beta cells in the pancreas produce the hormone insulin naturally. A basal insulin level is augmented in non-diabetic people by rises in insulin levels after meals. The metabolic alterations as the body shifts from a postabsorptive to an absorptive state are caused when postprandial insulin increases. Insulin stimulates amino acid uptake by the liver, muscle, and adipose tissue, which increases cellular uptake of glucose, especially in muscle and fatty tissues. Insulin also promotes energy storage through glycogenesis, fights against the catabolism of energy stores, increases DNA replication and protein synthesis, and modifies the activity of many enzymes involved in glycogen synthesis and glycolysis. The effects of growth hormone, including protein synthesis, cell division, and DNA synthesis, require insulin, which also stimulates growth.

Insulin aspart is used to simulate postprandial insulin increases in diabetics.

Its effect lasts 4-5 hours, reaching its peak 60-90 minutes after subcutaneous injection.

Pharmacokinetics:

Absorption

The median time to maximal insulin aspart concentration in these experiments was 40 to 50 minutes against 80 to 120 minutes for ordinary human insulin, respectively, in tests of healthy volunteers and patients with type 1 diabetes. When administered subcutaneously, Insulin Aspart absorbs more quickly than human insulin, acts more quickly, and lasts less time than conventional human insulin. Maximum concentration is attained after 40 to 50 minutes. In individuals with type 1 diabetes, the mean maximal concentration (Cmax) was 82 mU/L when a 0.15 U/kg body weight was administered. No effect is made on the amount or rate of absorption by the injection site.

Distribution

Unlike conventional human insulin, insulin aspart has a relatively small (10%) affinity for plasma proteins.

Protein-bound: 10%, similar to ordinary insulin (not bound to serum binding protein, but present in plasma as a monomer).

Metabolism and Elimination

An intravenous infusion of either the Insulin Aspart or regular human insulin was given to 17 healthy Caucasian male patients between 18 and 40 in a randomised, double-blind, crossover research. The infusion lasted 120 minutes. The mean results for the Insulin Aspart group and the standard human insulin group for mean insulin clearance were 1.2 L/h/kg.

Insulin Aspart was disposed of with an average apparent half-life of 81 minutes in healthy male volunteers (n=24) following subcutaneous injection.

Liver (>50%); kidney (30%); adipose tissue/muscle (20%)

Half-life: 81 min (Novolog SC); 1.1 hr (Fiasp)

Excretion: Urine

• Hermansen, K., Bohl, et al. Insulin Aspart in the Management of Diabetes Mellitus: 15 Years of Clinical Experience. Drugs 76, 41–74 (2016). https://doi.org/10.1007/s40265-015-0500-0
• Klonoff, David C et al. “A randomized, multicentre trial evaluating the efficacy and the safety of the fast-acting insulin aspart in continuous subcutaneous insulin infusion in adults with type 1 diabetes (onset 5).” Diabetes, obesity & metabolism vol. 21,4 (2019): 961-967. doi:10.1111/dom.13610
• Mathieu, Chantal et al. “Efficacy and safety of fast-acting insulin aspart in comparison with insulin aspart in type 1 diabetes (onset 1): A 52-week, randomized, treat-to-target, phase III trial.” Diabetes, obesity & metabolism vol. 20,5 (2018): 1148-1155. doi:10.1111/dom.13205
• Blevins, T.C., Raiter, Y., Sun, B. et al. Immunogenicity, Efficacy, and Safety of Biosimilar Insulin Aspart (MYL-1601D) Compared with the Originator Insulin Aspart (Novolog®) in Patients with Type 1 Diabetes After 24 Weeks: A Randomized Open-Label Study. BioDrugs 36, 761–772 (2022). https://doi.org/10.1007/s40259-022-00554-6

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